**5. Acknowledgments**

This work was supported by Texas Tech University Health Sciences Center grant.

Cell Cycle and DNA Damage Response in Postmitotic Neurons 259

Bartek, J. & Lukas, J. (2007). DNA damage checkpoints: from initiation to recovery or

Bartek, J.; Lukas, J. & Bartkova, J. (2007). DNA damage response as an anti-cancer barrier:

Bartkova, J.; Horejsí, Z.; Koed, K.; Krämer, A.; Tort, F.; Zieger, K.; Guldberg, P.; Sehested, M.;

Barzilai, A.; Biton, S. & Shiloh, Y. (2008). The role of the DNA damage response in neuronal

Barzilai A. (2010). DNA damage, neuronal and glial cell death and neurodegeneration. *Apoptosis*, Vol.15, No.11, (November 2010), pp.1371-1381. ISSN 2043-7103 Bazzi, M.; Mantiero, D.; Trovesi, C.; Lucchini, G. & Longhese, M.P. (2010).

Glc7/protein phosphatase 1 promotes recovery from inhibition of DNA replication. *Mol Cell* 

Becker, E.B. & Bonni, A. (2004). Cell cycle regulation of neuronal apoptosis in development and disease. *Prog Neurobiol*, Vol.72, No.1, (January 2004), pp.1-25, ISSN 1501-9174 Bekker-Jensen, S.; Lukas, C.; Melander, F.; Bartek, J. & Lukas, J. (2005). Dynamic assembly

Bennett, C.B.; Lewis, A.L.; Baldwin, K.K. & Resnick, M.A. (1993). Lethality induced by a

Bill, C.A.; Grochan, B.M.; Vrdoljak, E.; Mendoza, E.A. & Tofilon, P.J. (1992). Decreased repair

Bitomsky, N. & Hofmann, T.G. (2009). Apoptosis and autophagy: Regulation of apoptosis by

Biton, S.; Dar, I.; Mittelman, L;. Pereg, Y.; Barzilai, A. & Shiloh, Y. (2006). Nuclear ataxia-

Biton, S.; Gropp, M.; Itsykson, P.; Pereg, Y.; Mittelman, L.; Johe, K.; Reubinoff, B. & Shiloh, Y.

*Res*, Vol.132, No.2, (November 1992), pp.254–258, ISSN 143- 8708

*Acad Sci U S A*, Vol.90, No.12, (June 1993), pp. 5613-5617, ISSN 851- 6308 Berkovich, E.; Monnat, R.J. Jr. & Kastan, M.B. (2007). Roles of ATM and NBS1 in chromatin

and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1. *J Cell Biol*, Vol.170, No.2, (July 2005), pp.201–211, ISSN 1600-9723 Bekker-Jensen, S.; Lukas, C.; Kitagawa, R.; Melander, F.; Kastan, M.B.; Bartek, J. & Lukas, J.

(2006). Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. *J Cell Biol*, Vol.173, No.2, (April 2006), pp.195-206,

single site-specific double-strand break in a dispensable yeast plasmid. *Proc Natl* 

structure modulation and DNA double-strand break repair. *Nat Cell Biol,* Vol.9,

of radiation-induced DNA double-strand breaks with cellular differentiation. *Radiat* 

DNA damage signalling - roles of p53, p73 and HIPK2. *FEBS J*, Vol.276, No.21,

telangiectasia mutated (ATM) mediates the cellular response to DNA double strand breaks in human neuron-like cells, *J Biol Chem*, Vol.281, No.25, (April 2006),

(2007). ATM-mediated response to DNA double strand breaks in human neurons

Vol.6, No.19, (July 2007), pp. 2344–2347, ISSN 1770-0066

Vol.434, No.7035, (April 2005), pp. 864-870. ISSN 1582-9956

*Biol*, Vol.30, No.1, (January 2010), pp.131-145, ISSN 1988-4341

2008), pp. 1010-1027. ISSN 1845-8000

Dephosphorylation of gamma H2A by

No.6, (May 2007), pp.683–690, ISSN 1748-6112

(September 2007), pp. 6074-6083, ISSN 1978-8416

pp.17482-17491, ISSN 1662-7474

1730-3408

ISSN 1661-8811

adaptation. *Curr Opin Cell Biol*, Vol.19, No.2, (February 2007), pp.238-245. ISSN

damage threshold and the concept of 'conditional haploinsufficiency'. *Cell Cycle*,

Nesland, J.M.; Lukas, C.; Ørntoft, T.; Lukas, J. & Bartek, J. (2005). DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. *Nature*,

development, organization and maintenance. *DNA Repair (Amst),* Vol.7, No.7, (May

#### **6. References**


Abbas, T. & Dutta, A. (2009). p21 in cancer: intricate networks and multiple activities. *Nat* 

Ahel, D.; Horejsí, Z.; Wiechens, N.; Polo, S.E.; Garcia-Wilson, E.; Ahel, I.; Flynn, H.; Skehel,

M.; West, S.C.; Jackson S.P.; Owen-Hughes, T. & Boulton, S.J. (2009). Poly(ADPribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. *Science*, Vol.325, No.5945, (August 2010), pp.1240-1243, ISSN 1966-1379 Al-Hakim, A.; Escribano-Diaz, C.; Landry, M.C.; O'Donnell, L.; Panier, S.; Szilard, R.K. &

Durocher, D. (2010). The ubiquitous role of ubiquitin in the DNA damage response. *DNA Repair (Amst),* Vol.9, No.12, (November 2010), pp.1229-1240, ISSN 2105-6014 Alvira, D.; Yeste-Velasco, M.; Folch, J.; Casadesús, G.; Smith, M.A.; Pallàs, M. & Camins, A.

(2007). Neuroprotective effects of caffeine against complex I inhibition-induced apoptosis are mediated by inhibition of the Atm/p53/E2F-1 path in cerebellar granule neurons. *J Neurosci Res*, Vol.85, No.14, (November 2007), pp.3079-3088,

proapoptotic factor Bax by Ku70-dependent deubiquitylation. *Proc Natl Acad Sci U* 

outer mitochondrial membrane? *Curr Opin Cell Biol*, Vol.18, No.6, (October 2006),

and cancer therapy-two sides of the same coin? *Nat Rev Cancer*, Vol.7, No.12,

Feddersen, R.M. (1998). The transcription factor E2F-1 in SV40 T antigen-induced cerebellar Purkinje cell degeneration. *Mol Cell Neurosci*, Vol.12, No.1-2, (September

Prives, C.; Reiss, Y.; Shiloh, Y.& Ziv, Y. (1998). Enhanced phosphorylation of p53 by ATM in response to DNA damage. *Science*, Vol.281, No.5383, (September 1998), pp.

mediated apoptosis and downregulated by p53 in a p21-dependent manner. *Cell*

damage. *Curr Opin Cell Biol*, Vol.13, No.6, (December 2001), pp.738-747, ISSN 1169-

Amsel, A.D.; Rathaus, M.; Kronman, N. & Cohen, H.Y. (2008). Regulation of the

Antignani, A. & Youle, R.J. (2006). How do Bax and Bak lead to permeabilization of the

Antoni, L.; Sodha, N.; Collins, I. & Garrett, M.D. (2007). CHK2 kinase: cancer susceptibility

Aressy, B. & Ducommun, B. (2008) Cell cycle control by the CDC25 phosphatases. *Anticancer Agents Med Chem*, Vol.8, No.8, (December 2008), pp.818-824, ISSN 1907-5563 Athanasiou, M.C.; Yunis, W.; Coleman, N.; Ehlenfeldt, R.; Clark, H.B.; Orr, H.T. &

Averbeck, N.B. & Durante, M. (2011). Protein acetylation within the cellular response to radiation. *J Cell Physiol*, Vol.226, No.4, (April 2011), pp.962-967, ISSN 2094-5393 Aylon, Y. & Oren, M. (2007). Living with p53, dying of p53. *Cell*, Vol.130, No.4, (August

Banin, S.; Moyal, L.; Shieh, S.; Taya, Y.; Anderson, C.W.; Chessa, L.; Smorodinsky, N.I.;

Baptiste-Okoh, N.; Barsotti, A.M. & Prives, C. (2008). Caspase 2 is both required for p53-

Bartek, J. & Lukas, J. (2001). Mammalian G1- and S-phase checkpoints in response to DNA

Bartek, J.; Lukas, C. & Lukas, J. (2004). Checking on DNA damage in S phase. *Nat Rev Mol* 

*Cycle*, Vol.7, No.9, (February 2008), pp.1133-1138, ISSN 1841-8048

*Cell Biol*, Vol.5, No.10, (October 2007), pp. 792-804, ISSN1545-9660

*S A*, Vol.105, No.13, (March 2008), pp. 5117-5122, ISSN 1836-2350

*Rev Cancer*, Vol.9, No.6, (June 2009), pp.400-414, ISSN 1944-0234

**6. References** 

ISSN 1763-8302

pp. 685-689, ISSN 1704-6225

1998), pp.16-28, ISSN 977-0337

2007), pp. 597-600, ISSN 1771-9538

1674–1677, ISSN 973-3514

8191

(December 2007), pp.925-936, ISSN 1800-4398


Cell Cycle and DNA Damage Response in Postmitotic Neurons 261

Cha, H.; Lowe, J.M.; Li, H.; Lee, .;, Belova, G.;, Bulavin, D.V. & Fornace, A.J. Jr. (2010). Wip1

Chan, T.A.; Hermeking, H.; Lengauer, C.; Kinzler, K.W. & Vogelstein, B. (1999). 14-3-3Sigma

Chan, T.A.; Hwang, P.M.; Hermeking, H.; Kinzler, K.W. & Vogelstein, B. (2000). Cooperative

Chao, C.; Wu, Z.; Mazur, S.J.; Borges, H.; Rossi, M.; Lin, T.; Wang, J.Y.; Anderson, C.W.;

Chapman, J.R. & Jackson, S.P. (2008). Phospho-dependent interactions between NBS1 and

Chappell, C.; Hanakahi, L.A.; Karimi-Busheri, F.; Weinfeld, M. & West, S.C. (2002).

Chen, J.; Peters, R.; Saha, P.; Lee, P.; Theodoras, A.; Pagano, M.; Wagner, G. & Dutta, A.

Chou, D.M., Adamson, B, Dephoure, N.E., Tan, X., Nottke, A.C., Hurov, K.E., Gygi, S.P.,

Chowdhury, I.; Tharakan, B. & Bhat, G.K. (2006). Current concepts in apoptosis: The

Chowdhury, D.; Xu, X.; Zhong, X.; Ahmed, F.; Zhong, J.; Liao, J.; Dykxhoorn, D.M.;

Ciccia, A. & Elledge, S.J. (2010). The DNA damage response: making it safe to play with knives. *Mol Cell,* Vol.40, No.2, (October 2010), pp.179-204, ISSN 2096-5415 Citarelli, M.; Teotia, S. & Lamb, R.S. (2010). Evolutionary history of the poly(ADP-ribose)

Clerici, M.; Mantiero, D.; Guerini, I.; Lucchini, G. & Longhese, M.P. (2008). The Yku70-Yku80

*EMBO Rep*, Vol.9, No.8, (June 2008), pp.795-801, ISSN 1858- 3988

1996), pp.8936-8941, ISSN 86-21537

2000), pp.1584-1588, ISSN 1088-7152

ISSN 1203-2095

6753, (October 1999), pp. 616-620, ISSN 1052-4633

(September 2006), pp. 6859-6869, ISSN 1694-3427

(May 1996), pp.1727–1733, ISSN 864-9992

2006), pp. 506-525, ISSN 1697-7376

pp.308-334, ISSN 2094-2953

(October 2010), pp. 18475- 18480, ISSN 2093-7877

Vol.31, No.1, (July 2008), pp. 33-46, ISSN 1861-4045

directly dephosphorylates gamma-H2AX and attenuates the DNA damage response. *Cancer Res*, Vol.70, No.10, (May 2010), pp.4112-2412, ISSN 204-60517 Chan, D.W. & Lees-Miller, S.P. (1996). The DNA-dependent protein kinase is inactivated by

autophosphorylation of the catalytic subunit. *J Biol Chem*, Vol.271, No.15, (April

is required to prevent mitotic catastrophe after DNA damage. *Nature*, Vol.401, No.

effects of genes controlling the G(2)/M checkpoint. *Genes Dev*, Vol.14, No.13, (July

Appella, E. & Xu, Y. (2006). Acetylation of mouse p53 at lysine 317 negatively regulates p53 apoptotic activities after DNA damage. *Mol Cell Biol*, Vol.26, No.18,

MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage.

Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining. *EMBO J*, Vol.21, No.11, (June 2002), pp. 2827- 2832,

(1996). A 39 amino acid fragment of the cell cycle regulator p21 is sufficient to bind PCNA and partially inhibit DNA replication in vivo. *Nucleic Acids Res*, Vol.24, No.9,

Colaiácovo, M.P., Elledge, S.J. (2010). A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. *Proc Natl Acad Sci U S A*, Vol.107, No.43,

physiological suicide program revisited. *Cell Mol Biol Lett*, Vol.11, No.4, (September

Weinstock, D.M.; Pfeifer, G.P. & Lieberman, J. (2008). A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication. *Mol Cell*,

polymerase gene family in eukaryotes. *BMC Evol Biol*, Vol.10, (October 2010),

complex contributes to regulate double-strand break processing and checkpoint

derived from stem cells. *DNA Repair (Amst),* Vol.6, No.1, (December 2006), pp.128- 134, ISSN 1717-8256


Biton, S.; Barzilai, A. & Shiloh, Y. (2008). The neurological phenotype of ataxia–

Blank, M. & Shiloh, Y. (2007). Programs for cell death: apoptosis is only one way to go. *Cell* 

Bonilla, C.Y.; Melo, J.A. & Toczyski, D.P. (2008). Colocalization of sensors is sufficient to

Brady, C.A. & Attardi, L.D. (2010). p53 at a glance. *J Cell Sci*, Vol.123, Pt.15, (August 2010),

Branzei, D. & Foiani, M. (2008). Regulation of DNA repair throughout the cell cycle. *Nat Rev Mol Cell Biol*, Vol.9, No.4, (February 2008), pp.297–308, ISSN 1828-5803 Brugarolas, J.; Moberg, K.; Boyd, S.D.; Taya, Y.; Jacks, T. & Lees, J.A. (1999). Inhibition of

Burma, S.; Chen, B.P.; Murphy, M.; Kurimasa, A. & Chen, D.J. (2001). ATM phosphorylates

Busino, L.; Chiesa, M.; Draetta, G.F. & Donzelli, M. (2004) Cdc25A phosphatase:combinatorial

Caelles, C.; Helmberg, A. & Karin, M. (1994) p53-dependentapoptosis in the absence of

Calsou, P.; Delteil, C.; Frit, P.; Drouet, J. & Salles, B. (2003). Coordinated assembly of Ku and

Castedo, M.; Perfettini, J.L.; Roumier, T.; Andreau, K.; Medema, R. & Kroemer, G. (2004).

Celeste, A.; Petersen, S.; Romanienko, P.J.; Fernandez-Capetillo, O.; Chen, H.T.; Sedelnikova,

Celeste, A.; Fernandez-Capetillo, O.; Kruhlak, M.J.; Pilch, D.R.; Staudt, D.W.; Lee, A.; Bonner,

*Cycle*, Vol.6, No.6, (March 2007), pp. 686-95, ISSN 1736-1099

No.45, (September 2001), pp.42462-42467, ISSN 1157-1274

134, ISSN 1717-8256

2008), pp.1028-1038, ISSN 1845-6574

pp.2527-2532, ISSN 2094-0128

1999), pp.1002–1007, ISSN 992-7683

2004), pp. 2050-2056, ISSN 1502-1892

(April 2004), pp. 2825-2837, ISSN 1507-7146

2002) pp.922–927, ISSN 1193-4988

2003), pp.675–679, ISSN 1279-2649

pp. 220-223, ISSN 802-8670

ISSN 1254-7193

No.3, (May 2008), pp.267–276, ISSN 1847-1973

derived from stem cells. *DNA Repair (Amst),* Vol.6, No.1, (December 2006), pp.128-

telangiectasia: solving a persistent puzzle. *DNA Repair (Amst),* Vol.7, No.7, (May

activate the DNA damage checkpoint in the absence of damage. *Mol Cell*, Vol.30,

cyclindependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1arrest after gamma-irradiation. *Proc Natl Acad Sci USA,* Vol.96, No.3, (February

histone H2AX in response to DNA double-strand breaks. *J Biol Chem*, Vol.276,

phosphorylation, ubiquitylation and proteolysis. *Oncogene*, Vol.23, No.11, (March

transcriptional activation of p53- target genes. *Nature*, Vol.370, No.6486, (July 1994),

p460 subunits of the DNA- dependent protein kinase on DNA ends is necessary for XRCC4-ligase IV recruitment. *J Mol Biol*, Vol.326, No.1, (February 2003), pp.93-103,

Cell death by mitotic catastrophe: a molecular definition. *Oncogene*, Vol.23, No.16,

O.A.; Reina-San-Martin, B.; Coppola, V.; Meffre, E.; Difilippantonio, M.J.; Redon, C.; Pilch, D.R.; Olaru, A.; Eckhaus, M.; Camerini-Otero, R.D.; Tessarollo, L.; Livak, F.; Manova, K.; Bonner ,W.M.; Nussenzweig, M.C. & Nussenzweig, A. (2002). Genomic instability in mice lacking histone H2AX. *Science,* Vol.296, No.5569, (May

R.F.; Bonner,W.M. & Nussenzweig, A. (2003). Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. *Nat Cell Biol,* Vol.5, No7, (July


Cell Cycle and DNA Damage Response in Postmitotic Neurons 263

Downs, J.A.; Lowndes, N.F. & Jackson, S.P. (2000). A role for Saccharomyces cerevisiae

Downs, J.A.; Allard, S.; Jobin-Robitaille, O.; Javaheri, A.; Auger, A.; Bouchard, N.; Kron, S.J.;

Downs, J.A.; Allard, S.; Jobin-Robitaille, O.; Javaheri, A.; Auger, A.; Bouchard, N.; Kron, S.J.;

Downs, J.A.; Nussenzweig, M.C. & Nussenzweig, A. (2007). Chromatin dynamics and the

Dupre, A.; Boyer-Chatenet, L. & Gautier, J. (2006). Two-step activation of ATM by DNA and

Durant S.T.; Cho, E.C. & La Thangue, N.B. (2009).p53 methylation—the argument is clear.

Dvir, A.; Peterson, S.R.; Knuth, M.W.; Lu, H. & Dynan, W.S. (1992). Ku autoantigen is the

el-Deiry, W.S.; Tokino, T.; Velculescu, V.E.; Levy, D.B.; Parsons, R.; Trent, J.M.; Lin, D.;

Ewen, M.E.; Sluss, H.K.; Sherr, C.J.; Matsushime, H.; Kato, J. & Livingston, D.M. (1993).

Falck, J.; Lukas, C.; Protopopova, M.; Lukas, J.; Selivanova, G. & Bartek, J. (2001). Functional

Falck, J.; Coates, J. & Jackson, S.P. (2005). Conserved modes of recruitment of ATM, ATR

Feddersen, R.M.; Ehlenfeldt, R.; Yunis, W.S.; Clark, H.B. & Orr, H.T. (1992). Disrupted

Ferguson, A.T.; Evron, E.; Umbricht, C.B.; Pandita, T.; Chan, T.A.; Hermeking, H.; Marks,

SV40 T antigen transgenic mice. *Neuron*, Vol.9, No.5, (November 1992), Feddersen, R.M.; Clark, H.B.; Yunis, W.S. & Orr, H.T. (1995). In vivo viability of postmitotic

cyclins. *Cell*, Vol.73, No.3, (May 1993), pp. 487–497, ISSN 834-3202

*Cell Cycle*, Vol.8, No.6, (March 2009), pp. 801-802, ISSN 1922-1494

No.6, (December 2004), pp.979-990, ISSN 15610740

1004, ISSN 1114-0636

990,ISSN 1561-0740

958, ISSN 1758-1578

2752

ISSN 1157-1648.

pp.605–611, ISSN 1575-8953

No.2, (April 1995), pp.153-167, ISSN 755-1567

pp.451–457, ISSN 1662-2404

pp.11920-11924, ISSN 146-5419

histone H2A in DNA repair. *Nature*, Vol.408, No.6815, (Decemeber 2000), pp.1001-

Jackson, S.P. & Côté, J. (2004). *Mol Cell,* Vol.16, No.6, (December 2004), pp.979-

Jackson, S.P. & Côté J. (2004). Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. *Mol Cell*, 2004 Dec 22;Vol.16,

preservation of genetic information. *Nature,* Vol.447, No.7147, (June 2007), pp.951-

the Mre11-Rad50-Nbs1 complex. *Nature Struct Mol Biol,* Vol. 13, No.5, (May 2006),

regulatory component of a template-associated protein kinase that phosphorylates RNA polymerase II. *Proc Natl Acad Sci U S A*, Vol.89, No.24, (December 1992),

Mercer, W.E.; Kinzler, K.W. & Vogelstein, B. (1993). WAF1, a potential mediator of p53 tumor suppression. *Cell*, Vol.75, No.4, (September 1993), pp.817-825, ISSN 824-

Functional interactions of the retinoblastoma protein with mammalian D-type

impact of concomitant versus alternative defects in the Chk2–p53 tumour suppressor pathway. *Oncogene*, Vol.20, No.39, (September 2001), pp.5503- 5510,

and DNA-PKcs to sites of DNA damage. *Nature*, Vol.434, No.7033, (March 2005),

cerebellar cortical development and progressive degeneration of Purkinje cells in

Purkinje neurons requires pRb family member function. *Mol Cell Neurosci*. Vol.6,

J.R.; Lambers, A.R.; Futreal, P.A.; Stampfer, M.R. & Sukumar, S. (2000). High frequency of hypermethylation at the 14-3-3sigma locus leads to gene silencing in

activation during the cell cycle. *EMBO Rep,* Vol.9, No.8, (July 2008), pp.810-818, ISSN 1860-0234


Cohen, H.Y.; Lavu, S.; Bitterman, K.J.; Hekking, B.; Imahiyerobo, T.A.; Miller, C.; Frye, R.;

Copani, A.; Sortino, M.A.; Caricasole, A.; Chiechio, S.; Chisari, M.; Battaglia, G.; Giuffrida-

Coppede, F & Migliore, L. (2010). DNA repair in premature aging disorders and

Costanzo, A.; Merlo, P.; Pediconi, N.; Fulco, M.; Sartorelli, V.; Cole, P.A.; Fontemaggi, G.;

Blandino, G.; Balsano, C. & Levrero, M. (2002). DNA damage-dependent acetylation of p73

Elledge, S. J. (1996). Cell cycle checkpoints: preventing an identity crisis. *Science,* Vol.274,

D'Amours, D.; Desnoyers, S.; D'Silva, I. & Poirier, G.G. (1999). Poly(ADP-ribosyl)ation

Das, S.; Boswell, S.A.; Aaronson, S.A. & Lee, S.W. (2008). P53 promoter selection: choosing

Deckbar, D.; Birraux, J.; Krempler, A.; Tchouandong, L.; Beucher, A.; Walker, S.; Stiff, T.;

de Jager, M.; van Noort, J.; van Gent, D.C.; Dekker, C.; Kanaar, R. & Wyman, C. (2001). *Mol Cell,* 2001 Nov;Vol.8, No.5, (November 2001), pp.1129-1135, ISSN 1174-1547 de Murcia, G. & Ménissier de Murcia, J. (1994). Poly(ADP-ribose) polymerase: a molecular

Demidenko, Z.N.; Korotchkina, L.G.; Gudkov, A.V. & Blagosklonny, M.V. (2010).

Deng, C.; Zhang, P.; Harper, J.; Elledge, S.J. & Leder, P. (1995). Mice lacking p21CIP1/WAF1

Ding, H.F.; McGill, G.; Rowan, S.; Schmaltz, C.; Shimamura, A. & Fisher, D.E. (1998).

of caspase activation by p53 protein in a cell-free system. *J Biol Chem*, Vol.273, No.43

Dobbelstein, M.; Strano, S.; Roth, J. & Blandino, G. (2005). p73-induced apoptosis: a question

*Cell Biol*, Vol.176, No.6, (March 2007), pp.749-755, ISSN 1735- 3355

Vol.107, No.21 (May 2010), pp.9660-9664, ISSN 2045-7898

Vol.82, No.4 (August 1995), pp. 675-684, ISSN 766-4346

(October 1998), pp.28378-28383, ISSN 977-4464

(June 2005), pp. 688-693, ISSN 1586-5923

ISSN 1860-0234

2029-8165

1821-2532

Fanciulli, M.; Schiltz, L.;

(March 2004), pp. 627-638, ISSN 1502-3334

(October 2002), pp. 2006-2008, ISSN 1239-7084

(January 2002), pp.175–186, ISSN 1180-4596

1999), pp.249-268, ISSN 1045-5009

Oncogene-dependent regulation

No.5293, (December 1996), pp. 1664-1672, ISSN 893-9848

activation during the cell cycle. *EMBO Rep,* Vol.9, No.8, (July 2008), pp.810-818,

Ploegh, H.; Kessler, B.M. & Sinclair, D.A. (2004). Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. *Mol Cell*, Vol.13, No.5,

Stella, A.M.; Vancheri, C. & Nicoletti, F. (2002). Erratic expression of DNA polymerases by beta-amyloid causes neuronal death. *FASEB J*, Vol.16, No.14,

neurodegeneration. *Curr Aging Sci*, Vol.3, No.1, (February 2010), pp.3-19, ISSN

dictates the selective activation of apoptotic target genes. *Mol Cell*, Vol.9, No.1,

reactions in the regulation of nuclear functions. *Biochem J*, Vol.342, Pt. 2, (September

between life and death. *Cell Cycle*, Vol.7, No.2, (October 2007), pp.154-157, ISSN

Jeggo, P. & Löbrich, M. (2007). Chromosome breakage after G2 checkpoint release. *J* 

nick-sensor. *Trends Biochem Sci,* Vol.19, No.4 (April 1994), pp172-176, ISSN 8016-868

Paradoxical suppression of cellular senescence by p53. *Proc Natl Acad Sci USA*,

undergo normal development, but are defective in G1 checkpoint control. *Cell*,

of compartments and cooperation. *Biochem Biophys Res Commun*, Vol.331, No.3


Cell Cycle and DNA Damage Response in Postmitotic Neurons 265

Groth, A.; Rocha, W.; Verreault, A. & Almouzni, G. (2007). Chromatin challenges during

Gu, Y.; Turck, C.W. & Morgan, D.O. (1993). Inhibition of CDK2 activity in vivo by an

Haince, J.F.; McDonald, D.; Rodrigue, A.; Déry, U.; Masson, J.Y.; Hendzel, M.J. & Poirier,

Hakem, R. (2008). DNA-damage repair; the good, the bad, and the ugly. *EMBO J*, Vol.27,

Hakmé, A.; Wong, H.K.; Dantzer, F. & Schreiber, V. (2008). The expanding field of

Hammel, M.; Yu, Y.; Mahaney, B.L.; Cai, B.; Ye, R.; Phipps, B.M.; Rambo, R.P.; Hura, G.L.;

Hammond, E.M.; Denko, N.C.; Dorie, M.J.; Abraham, R.T. & Giaccia, A.J. (2002). Hypoxia

Harper, J.W.; Adami, G.R.; Wei, N.; Keyomarsi, K. & Elledge, S.J. (1993). The p21 Cdk-

Henrique, R.; Jeronimo, C.; Hoque, M.O.; Carvalho, A.L.; Oliveira, J.; Teixeira, M.R.; Lopes,

Heo, K.; Kim, H.; Choi, S.H.; Choi, J.; Kim, K.; Gu, J.; Lieber, M.R.; Yang, A.S. & An, W.

Herrup, K.; Neve, R.; Ackerman, S.L. & Copani, A. (2004). Divide and die: cell cycle events

Herzog, K.H.; Chong, M.J.; Kapsetaki, M.; Morgan, J.I. & McKinnon, P.J. (1998).

*Chem*, Vol.285, No.2, (November 2009), pp.1414-1423, ISSN 1989-3054 Hammet, A.; Magill, C.; Heierhorst, J. & Jackson, S.P. (2007). Rad9 BRCT domain interaction

*Rep*, Vol.8, No.9, (August 2007), pp.851-857, ISSN 1772-1446

Vol.75, No.4, (November 1993), pp.805-816, ISSN 824-2751

20509

pp.707–710, ISSN 825-9216

ISSN 1892-7583

2008), pp.1197-1208, ISSN 1802-5084

2002), pp.1834-1843, ISSN 1186-5061

(April 2008), pp.86-97, ISSN 1840-6329

269, ISSN 1581-2243

9239, ISSN 1549-6657

9582124

No.4, (February 2008), pp.589-605, ISSN 1828-5820

DNA replication and repair. *Cell,* Vol.128, (February 2007), pp. 721-733, ISSN 173-

associated 20K regulatory subunit. *Nature*, Vol.366, No.6456, (December 1993),

G.G. (2008). PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. *J Biol Chem*, Vol.283, No.21, (November

poly(ADP-ribosyl)ation reactions. 'Protein Modifications: Beyond the Usual Suspects' Review Series. *EMBO Rep*, Vol.9, No.11, (October 2008), pp.1094-100,

Pelikan, M.; So, S.; Abolfath, R.M.; Chen, D.J.; Lees-Miller, S.P. & Tainer, J.A. (2009). Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex. *J Biol* 

with phosphorylated H2AX regulates the G1 checkpoint in budding yeast. *EMBO* 

links ATR and p53 through replication arrest. *Mol Cell Biol*, Vol.22, No.6, (March

interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. *Cell*,

C. & Sidransky, D. (2005). Frequent 14-3-3sigma promoter methylation in benign and malignant prostate lesions. *DNA Cell Biol*, Vol.24, No.4, (April 2005), pp.264-

(2008). FACT-mediated exchange of histone variant H2AX regulated by phosphorylation of H2AX and ADP-ribosylation of Spt16. *Mol Cell*, Vol.30, No.1,

as triggers of nerve cell death. *J Neurosci*, Vol.24, No.42, (October 2004), pp.9232-

Requirement for Atm in ionizing radiation- induced cell death in the developing central nervous system. *Science*, Vol.280, No.55366, (May 1998), pp.1089–1091, ISSN

breast cancer. *Proc Natl Acad Sci USA*, Vol.97, No.22, (May 2000), pp. 6049-6054, ISSN 1081-1911


Fernandez-Capetillo, O.; Lee, A.; Nussenzweig, M.; & Nussenzweig, A. (2004). H2AX: the

Field, S.J.; Tsai, F.; Kuo, F.; Zubiaga, A.M.; Kaelin, Jr. W.G.; Livingston, D.M.; Orkin, S.H. &

Gagné, J.P.; Hendzel, M.J.; Droit, A. & Poirier, G.G. (2006). The expanding role of poly(ADP-

Garner, E. & Raj, K. (2008). Protective mechanisms of p53–p21–pRb proteins against DNA

Gell, D. & Jackson SP. (1999). Mapping of protein-protein interactions within the DNA-

Gobbel, G.T.; Bellinzona, M.; Vogt, A.R.; Gupta, N.; Fike, J.R. & Chan, P.H. (1998). Response

Gorgoulis, V.; Vassiliou, L.V.; Karakaidos, P.; Zacharatos, P.; Kotsinas, A.; Liloglou, T.;

Gorodetsky, E.; Calkins, S.; Ahn, J. & Brooks, P.J. (2007). ATM, the Mre11/Rad50/Nbs1

Gottlieb, T.M. & Jackson, S.P. (1993). The DNA-dependent protein kinase: requirement for

Gottschalk, A.J.; Timinszky, G.; Kong, S.E.; Jin, J.; Cai, Y.; Swanson, S.K.; Washburn, M.P.;

Gottifredi, V.; Shieh, S.Y.; Taya, Y. & Prives, C. (2001). p53 accumulates but is functionally

Green, D.R. & Kroemer, G. (2009). Cytoplasmic functions of the tumour suppressor p53. *Nature*, Vol.458, No.7242, (April 2009), pp.1127-1130, ISSN 1940-7794

Vol.18, No.2, (April 2006), pp.145-151, ISSN 1651-6457

No.7035, (April 2005), pp. 907-913, ISSN 1582-9965

(January 2001), pp.1036-1041, ISSN 1115-8590

1999), pp. 3494-3502, ISSN 1044-6239

pp.1698-1707, ISSN 1770-6468

131-142, ISSN 842-2676

ISSN 1966- 6485

proliferation. *Cell*, Vol.85, No.4, (May 1996), pp. 549–561, ISSN 865-3790 Fishel, M.L.; Vasko, M.R. & Kelley, M.R. (2007). DNA repair in neurons: so if they don't

ISSN 1081-1911

1687-9837

ISSN 1823-5223

941-2495

pp.959–967, ISSN 1527-9782

breast cancer. *Proc Natl Acad Sci USA*, Vol.97, No.22, (May 2000), pp. 6049-6054,

histone guardian of the genome. *DNA Repair (Amst)*, Vol.3, No.8-9, (Aug-Sep 2004),

Greenberg, M.E. (1996). E2F-1 functions in mice to promote apoptosis and suppress

divide what's to repair? *Mutat Res,* Vol.614, No.1-2, (August 2006), pp.24–36, ISSN

ribose) metabolism: current challenges and new perspectives. *Curr Opin Cell Biol*,

damage-induced cell death. *Cell Cycle*, Vol.7, No.3, (November 2008), pp.277–282,

dependent protein kinase complex. *Nucleic Acids Res*, Vol.27, No.17, (September

of postmitotic neurons to X- irradiation: implications for the role of DNA damage in neuronal apoptosis. *J Neurosci*, Vol.18, No.1, (January 1998), pp.147–155, ISSN,

Venere, M.; Ditullio, R.A. Jr.; Kastrinakis, N.G.; Levy, B.; Kletsas, D.; Yoneta, A.; Herlyn, M.; Kittas, C. & Halazonetis, T.D. (2005). Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. *Nature*, Vol.434,

complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain. *DNA Repair (Amst)*, Vol.6, No.11, (August 2007),

DNA ends and association with Ku antigen. *Cell*, Vol.72, No.1, (January 1993), pp.

Florens, L.; Ladurner, A.G.; Conaway, J.W. & Conaway, R.C. (2009). Poly(ADPribosyl)ation directs recruitment and activation of an ATP- dependent chromatin remodeler. *Proc Natl Acad Sci U S A*, Vol.106, No.33, (August 2009), pp. 13770-13774,

impaired when DNA synthesis is blocked. *Proc Natl Acad Sci USA,* Vol.98, No.3,


Cell Cycle and DNA Damage Response in Postmitotic Neurons 267

Jha, S.; Shibata, E. & Dutta, A. (2008). Human Rvb1/Tip49 is required for the histone

Jin, Y.H.; Yoo, K.J.; Lee, Y.H. & Lee SK. (2000). Caspase 3-mediated cleavage of

Johnson, D.G.; Schwarz, J.K.; Cress, W.D. & Nevins, J.R. (1993). Expression of transcription

Jungmichel, S. & Stucki, M. (2010). MDC1: The art of keeping things in focus. *Chromosoma,*

Kaidi, A.; Weinert, B.T.; Choudhary, C. & Jackson, S.P. (2010). Human SIRT6 promotes DNA

Karagiannis, T. C. & El-Osta, A. (2007). Chromatin modifications and DNA double-strand

Kastan, M.B. & Bartek, J. (2004). Cell-cycle checkpoints and cancer. *Nature*, Vol. 432, No.

Khanna, K.K. & Jackson, S.P. (2001). DNA double-strand breaks: signaling, repair and the

Khanna, K. K.; Lavin, M. F., Jackson, S. P. & Mulhern, T. D. (2001). ATM, a central controller

Kim, D. & Tsai, L.H. (2009). Linking cell cycle reentry and DNA damage in

Kim, M.Y.; Zhang, T. & Kraus, W.L. (2005). Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying'

Knights, C.D.; Catania, J.; Di Giovanni, S.; Muratoglu, S.; Perez, R.; Swartzbeck, A.; Quong,

Koch, C.A.; Agyei, R.; Galicia, S.; Metalnikov, P.; O'Donnell, P.; Starostine, A.; Weinfeld, M.

Kolas, N.K.; Chapman, J.R.; Nakada, S.; Ylanko, J.; Chahwan, R.; Sweeney, F.D.; Panier, S.;

*Cell Biol*, Vol.173, No.4, (May 2006), pp.533-544, ISSN 1671-7128

(September 2004), pp. 3874–3885, ISSN 1538-5968

(February 2008), pp. 2690-2700, ISSN 1828-5460

(September 2000), pp.30256–30263, ISSN 1088-4382

Vol.119, No.4, (March, 2010), pp.337-349. ISSN 2022-4865

7015, (November 2004), pp.316– 323, ISSN 1554-9093

(September, 1993), pp.349-352. ISSN 837-7827

2010), pp.1348-1353, ISSN 2082-9486

2001), pp.1052–1065, ISSN 1168-7884

200, ISSN 1715-1702

2102

1968-6210

1967, ISSN 1614-0981

acetyltransferase activity of Tip60/NuA4 and for the downregulation of phosphorylation on H2AX after DNA damage. *Mol Cell Biol*, Vol.28, No.8,

p21WAF1/CIP1 associated with the cyclin A- cyclin-dependent kinase 2 complex is a prerequisite for apoptosis in SK-HEP-1 cells. *J Biol Chem*, Vol.275, No.39,

factor E2F1 induces quiescent cells to enter S phase. *Nature*, Vol.365, No.6444,

end resection through CtIP deacetylation. *Science*, Vol.329, No.5997, (September

breaks: the current state of play. *Leukemia,* Vol.21, No.2, (December 2006), pp.195–

cancer connection. *Nat Genet*, Vol. 27, No.3, (March 2001), pp.247–254, ISSN 1124-

of cellular responses to DNA damage. *Cell Death Differ,* Vol*.* 8, No. 11, (November

neurodegeneration. *Ann N Y Acad Sci*, Vol*.* 1170, (July 2009), pp. 674-679, ISSN

NAD+ into a nuclear signal. *Genes Dev*, Vol.19, No.17, (September 2005), pp.1951-

A.A.; Zhang, X.; Beerman, T.; Pestell, R.G. & Avantaggiati, M.L. (2006). Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate. *J* 

& Durocher, D. (2004).Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV. *EMBO J*, Vol. 23, No.19,

Mendez, M.; Wildenhain, J.; Thomson, T.M.; Pelletier, L.; Jackson, S.P. & Durocher, D. (2007). Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. *Science,* Vol.318, No.5856, (November 2007), pp.1637-1640, ISSN 1800-6705


Hirao, A.; Kong, Y.Y.; Matsuoka, S.; Wakeham, A.; Ruland, J.; Yoshida, H.; Liu, D.; Elledge,

Hoffmann, I.; Clarke, P.R.; Marcote, M.J.; Karsenti, E. & Draetta, G. (1993). Phosphorylation

Höglinger, G.U.; Breunig, J.J.; Depboylu, C.; Rouaux, C.; Michel, P.P.; Alvarez-Fischer, D.;

Houtgraaf, J.H.; Versmissen, J. & van der Giessen, W.J. (2006). A concise review of DNA

Huang, J.Y.; Chen, W.H.; Chang, Y.L.; Wang, H.T.; Chuang, W.T & Lee SC. (2006).

*Nucleic Acids Res*, Vol.34, No.8, (May 2006), pp.2398-2407, ISSN 1668- 2447 Huen, M.S. & Chen, J. (2008). The DNA damage response pathways: at the crossroad of protein modifications. *Cell Res,* Vol.18, No.1, (January 2008), pp.8-16, ISSN 1808-7291 Husseman, J.W.; D. Nochlin, D. & Vincent, I. (2000). Mitotic activation: a convergent

Iaquinta, P.J. & Lees, J.A. (2007). Life and death decisions by the E2F transcription factors. *Curr Opin Cell Biol*, Vol.19, No.6, (November 2007), pp. 649–657, ISSN 1803-2011 Ikura, T.; Tashiro, S.; Kakino, A.; Shima, H.; Jacob, N.; Amunugama, R.; Yoder, K.; Izumi, S.;

Jackson, S.P. (2009). The DNA-damage response: new molecular insights and new

Jackson, S.P. & Bartek, J. (2009). The DNA-damage response in human biology and disease. *Nature,* Vol.461, No.7267, (October 2009), pp.1071-1078, ISSN 1984-7258 Jansson, M.; Durant, S.T.; Cho, E.C.; Sheahan, S.; Edelmann, M.; Kessler, B. & La Thangue,

Jazayeri, A.; Falck, J.; Lukas, C.; Bartek, J.; Smith, G.C.; Lukas, J. & Jackson, S.P. (2006). ATM-

breaks *Nat Cell Biol*, Vol.8, No.1, (December 2005), pp.37-45, ISSN 1632-7781 Jeong, J.; Juhn, K.; Lee, H.; Kim, S.H.; Min, B.H.; Lee, K.M.; Cho, M.H.; Park, G.H. & Lee,

*Mol Med*, Vol.39, No.1, (February 2007), pp.8-13, ISSN 1733-4224

(October 2009), pp.25-27, ISSN 1980- 4750

No.3, (July-September 2006), pp.165-172, ISSN 1694-5824

No.6, (November 2000), pp.815-828, ISSN 1112-4425

No.12, (November 2008), pp. 1431-1439, ISSN 1901-1621

842-8594

494, ISSN 1984-7258

S.J. & Mak, T.W. (2000). DNA damage-induced activation of p53 by the checkpoint kinase Chk2. *Science*, Vol.287, No.5459, (March 2000), pp.1824- 1827, ISSN 1071-0310

and activation of human cdc25-C by cdc2–cyclin B and its involvement in the selfamplification ofMPFatmitosis. *EMBOJ*, Vol.12, No.1, (January 1993), pp.53-63, ISSN

Boutillier, A.L.; Degregori, J.; Oertel, W.H.; Rakic, P.; Hirsch, E.C. & Hunot, S. (2007). The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease. *Proc Natl Acad Sci USA*, Vol.104, No.9, (February 2007), pp.25-27, ISSN 1736-0686 Hopfner, K.P. (2009). DNA double-strand breaks come into focus. *Cell*, Vol.139, No.1,

damage checkpoints and repair in mammalian cells. *Cardiovasc Revasc Med*, Vol.7,

Modulation of nucleosome-binding activity of FACT by poly(ADP-ribosyl)ation.

mechanism for a cohort of neurodegenerative diseases. *Neurobiol Aging,* Vol.21,

Kuraoka, I.; Tanaka, K.; Kimura, H.; Ikura, M.; Nishikubo, S.; Ito, T.; Muto, A.; Miyagawa, K.; Takeda, S.; Fishel, R.; Igarashi, K. & Kamiya, K. (2007). DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. *Mol Cell Biol*, Vol.27, No.20, August 2007), pp.7028-7040, ISSN 1770-9392

approaches to cancer therapy. *Biochem Soc Trans,* Vol*.*37, Pt.3, (June 2009), pp. 483–

N.B. (2008). Arginine methylation regulates the p53 response. *Nat Cell Biol*, Vol.10,

and cell cycle-dependent regulation of ATR in response to DNA double-strand

K.H. (2007). SIRT1 promotes DNA repair activity and deacetylation of Ku70. *Exp* 


Cell Cycle and DNA Damage Response in Postmitotic Neurons 269

Le Cam, L.; Linares, L.K.; Paul, C.; Julien, E.; Lacroix, M.; Hatchi, E.; Triboulet, R.; Bossis, G.;

Lee, J.H. & Paull, T.T. (2005). ATM activation by DNA double-strand breaks through the

Lee, J.H., Choy, M.L., Ngo, L., Foster, S.S., Marks, P.A. (2010). Histone deacetylase inhibitor

Lee, Y.; Chong, M.J. & McKinnon PJ. (2001). Ataxia telangiectasia mutated–dependent

Lee, Y. & McKinnon, P.J. (2007). Responding to DNA double strand breaks in the nervous system. *Neuroscience*, Vol.145, No.4, (April 2007), pp.1365-1374, ISSN 16934412 Leroy, C.; Lee, S.E.; Vaze, M.B.; Ochsenbien, F.; Guerois, R.; Haber, J.E. & Marsolier-Kergoat,

Levine, A.J. & Oren, M. (2009). The first 30 years of p53: growing ever more complex. *Nat Rev Cancer*, Vol.9, No.10, (October 2009), pp.749-758, ISSN 1977-6744 Levkau, B.; Koyama, H.; Raines, E.W.; Clurman, B.; Herren, B.; Orth, K.; Roberts, J.M. &

Li, X.; Corsa, C.A.; Pan, P.W.; Wu, L.; Ferguson, D.; Yu, X.; Min, J. & Dou, Y. (2010). MOF

Lieber MR. (2010). The mechanism of double-strand DNA break repair by the

Lisby, M; Barlow, J.H.; Burgess, R.C. & Rothstein, R. (2004). *Cell,* Vol.118, No.6, (September

Vol.5, No.6, (December 2000), pp.523–529, ISSN 1130-3911

Vol.1, No.4, (March 1998), pp.553-563, ISSN 966-0939

(September 2010), pp.5335-5347, ISSN 2083-7706

2004), pp.699-713, ISSN 1536- 9670

1953-6131

ISSN 1579-0808

6693, ISSN 1151-7258

ISSN 2019-2759

pp.1414-1423, ISSN 1989-3054

Shmueli, A.; Rodriguez, M.S.; Coux, O. & Sardet, C. (2006). E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. *Cell*, Vol.127, No.4, (November 2006), pp. 775-788, ISSN 1711-0336 Lee, E.W.; Lee, M.S.; Camus, S.; Ghim, J.; Yang, M.R.; Oh, W.; Ha, N.C.; Lane, D.P. & Song, J.

(2009).Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cyclearrest and apoptosis, *EMBO J*,. Vol.28, No.14, (June 2009), pp.2100–2113, ISSN

Mre11-Rad50-Nbs1 complex. *Science*, Vol.308, No. 5721, (March 2005), pp.551-554,

induces DNA damage, which normal but not transformed cells can repair. *Proc Natl Acad Sci U S A*, Vol.107, No.33, (August 2010), pp.14639-14644, ISSN 2067-9231 Lee, S.M.; Bae, J.H.; Kim, M.J.; Lee, H.S.; Lee, M.K.;Chung, B.S.; Kim, D.W.; Kang, C.D. &

Kim, S.H. (2007). Bcr-Abl- independent imatinib-resistant K562 cells show aberrant protein acetylation and increased sensitivity to histone deacetylase inhibitors. *J Pharmacol Exp Ther*, Vol.322, No.3, (June 2007), pp.1084-1092, ISSN 1756-9822 Lee, Y. & McKinnon, P.J. (2000). ATM dependent apoptosis in the nervous system. *Apoptosis* 

apoptosis after genotoxic stress in the developing nervous system is determined by cellular differentiation status. *J Neurosci*, Vol.21, No.17, (September 2001), pp.6687–

M.C. (2003). PP2C phosphatases Ptc2 and Ptc3 are required for DNA checkpoint inactivation after a double-strand break. *Mol Cell*, Vol.285, No.2, (November 2003),

Ross, R. (1998). Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. *Mol Cell*,

and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. *Mol Cell Biol*, Vol.30, No.22,

nonhomologous DNA end-joining pathway. *Annu Rev Biochem*, Vol.79, pp. 181-211,


Korotchkina, L.G.; Leontieva, O.V.; Bukreeva, E.I.; Demidenko, Z.N.; Gudkov, A.V. &

Kraemer, K.H.; Sander, M. & Bohr, V.A. (2007). New areas of focus at workshop on human

Kraljevic Pavelic, S.; Cacev, T. & Kralj, M. (2008). A dual role of p21waf1/cip1 gene in

Krishnakumar, R. & Kraus, W.L. (2010). The PARP side of the nucleus: molecular actions,

Kouzarides, T. (2007).Chromatin modifications and their function. *Cell,* Vol.128, No.4,

Kruman, I.I. (2004). Why do neurons enter the cell cycle? *Cell Cycle*, Vol.3, No.6, (June 2004),

Kruman, I.I., Wersto, R.P.; Cardozo-Pelaez, F.; Smilenov, L.; Chan, S.; Chrest, F.; Emokpae,

Kuan, C.Y.; Schloemer, A.J.; Lu, A.; Burns, K.A.; Weng, W.L.; Williams, M.T.; Strauss, K.I.;

Kumagai, A. & Dunphy, W.G. (2006) How cells activate ATR. *Cell Cycle*, Vol.5, No.12, (June

Kuroda, Y.; Aishima, S.; Taketomi, A.; Nishihara, Y.; Iguchi, T.; Taguchi, K.; Maehara, Y. &

Kusch, T.; Florens, L.; Macdonald, W.H.; Swanson, S.K.; Glaser, R.L.; Yates, J.R. 3rd.;

Lal, A.; Abdelmohsen, K.; Pullmann, R.; Kawai, T.; Galban, S.; Yang, X.; Brewer, G. &

Lavin, M.F. & Kozlov, S. (2007). DNA damage-induced signalling in ataxia–telangiectasia

No.5704, (November 2004), pp.2084-2087, ISSN 1552-8408

Vol. 275, No.30, (July 2000), pp. 23106-23112, ISSN 1076-7298

No.6, (June 2010), pp. 344-352, ISSN 2060-6252

No.9, (May 2008), pp. 576-590, ISSN 1848-3502

(February 2007), pp.693–705, ISSN 1732-0507

pp.8-24, ISSN 2060-3072

pp. 769-773, ISSN 1513-6759

2006), pp. 1265-1268, ISSN 1676- 0665

561, ISSN 1498-0204

ISSN 1556-4594

1739-1729

ISSN 1751-2070

Vol.128, No.2, (February 2007), pp.229-235, ISSN 1736-1460

Blagosklonny, M.V. (2010).The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. *Aging (Albany NY)*, Vol.2,

diseases involving DNA repair deficiency and premature aging. *Mech Ageing Dev*,

apoptosis of HEp-2 treated with cisplatin or methotrexate. *Cancer Gene Ther*, Vol.15,

physiological outcomes, and clinical targets. *Mol Cell*, Vol.39, No.1, (July 2010),

R. Jr.; Gorospe, M. & Mattson, M.P. (2004). Cell cycle activation linked to neuronal cell death initiated by DNA damage. *Neuron*, Vol.41, No.4, (February 2004), pp.549–

Vorhees, C.V.; Flavell, R.A.; Davis, R.J.; Sharp, F.R. & Rakic, P. (2004). Hypoxiaischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. *J Neurosci*, Vol.24, No.47, (November 2004), pp. 10763-10772,

Tsuneyoshi, M. (2007). 14-3- 3sigma negatively regulates the cell cycle, and its downregulation is associated with poor outcome in intrahepatic cholangiocarcinoma. *Hum Pathol,* Vol.38, No.7, (March 2007), pp. 1014-1022, ISSN

Abmayr, S.M.; Washburn, M.P. & Workman, J.L. (2004). Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. *Science*, Vol.306,

Gorospe, M. (2006). Posttranscriptional derepression of GADD45alpha by genotoxic stress. *Mol Cell*, Vol.22, No.1, (April 2006), pp.117-128, ISSN 1660-0875 Laronga, C.; Yang, H.Y.; Neal, C. & Lee, M.H. (2000). Association of the cyclin-dependent

kinases and 14-3-3sigma negatively regulates cell cycle progression. *J Biol Chem*,

and related syndromes. *Radiother Oncol,* Vol. 83, No.3, (May 2007), pp.231–237,


Cell Cycle and DNA Damage Response in Postmitotic Neurons 271

McKinnon, P.J. (2001). Ataxia telangiectasia: new neurons and ATM. *Trends Mol Med*, Vol.7,

McMurray, C.T. (2005). To die or not to die: DNA repair in neurons. *Mutat Res*, Vol.577,

McShea, A.; Wahl, A.F. & Smith, M.A. (1999). Re-entry into the cell cycle: a mechanism for

Meek, D.W. (1994). Post-translational modification of p53. *Semin Cancer Biol*, Vol.5, No.3,

Melander, F.; Bekker-Jensen, S.; Falck, J.; Bartek, J.; Mailand, N. & Lukas, J. (2008).

Melino, G. (2003) p73, the ''assistant'' guardian of the genome? *Ann N Y Acad Sci*, Vol.1010,

Meng, S.; Arbit, T.; Veeriah, S.; Mellinghoff, I.K.; Fang, F.; Vivanco, I.; Rohle, D. & Chan, T.A.

Merkle, D.; Douglas, P.; Moorhead, G.B.; Leonenko, Z.; Yu, Y.; Cramb, D.; Bazett-Jones, D.P.

Milczarek, G.J.; Martinez, J. & Bowden, G.T. (1997). p53 Phosphorylation: biochemical and functional consequences. *Life Sci*, Vol.60, No.1, pp.1-11, ISSN 899-5526 Messick TE, Greenberg RA. (2009). The ubiquitin landscape at DNA double-strand breaks. *J Cell Biol*, Vol.187, No.3, (November 2009), pp.319-326. ISSN 1994-8475 Mihara, M.; Erster, S.; Zaika, A.; Petrenko, O.; Chittenden, T.; Pancoska, P. & Moll, U.M.

Miller, S.A.; Mohn, S.E. & Weinmann, A.S. (2010). Jmjd3 and UTX play a demethylase-

Mimori, T. & Hardin, J.A.(1986). Mechanism of interaction between Ku protein and DNA. *J Biol Chem,* Vol.261, No,22, (August 1986), pp.10375-10379, ISSN 301-5926 Morselli, E.; Galluzzi, L.; Kepp, O. & Kroemer, G. (2009). Nutlin kills cancer cells via

Mortusewicz, O.; Amé, J.C.; Schreiber, V. & Leonhardt, H. (2007). Feedback-regulated

Moynahan, M.E.; Chiu, J.W.; Koller, B.H. & Jasin, M. (1999). Brca1 controls homology-directed DNA repair. *Mol Cell*, Vol. 4, No.4, (October 1999), pp.511-518, ISSN 1054-9283

Vol.41, No.42, (October 2002), pp.12706-12714, ISSN 1237-9113

neurodegeneration in Alzheimer disease. *Med Hypotheses*, Vol.52, No.6, (June 1999),

Phosphorylation of SDT repeats in the MDC1 N terminus triggers retention of NBS1 at the DNA damage-modified chromatin. *J Cell Biol,* Vol.181, No.2, (April

(2009). 14-3-3sigma and p21 synergize to determine DNA damage response following Chk2 inhibition. *Cell Cycle*, Vol.8, No.14, (July 2009), pp. 2238- 2246, ISSN

& Lees-Miller, S.P. (2002). The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation. *Biochemistry*,

(2003) p53 has a direct apoptogenic role at the mitochondria. *Mol Cell*, Vol.11, No.3,

independent role in chromatin remodeling to regulate T-box family memberdependent gene expression. *Mol Cell*, Vol.40, No.4, (November 2010), pp.594-605,

mitochondrial p53. *Cell Cycle*, Vol.8, No.11, (June 2009), pp. 1647-1648, ISSN 1944-

poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells. *Nucleic Acids Res*, Vol.35, No.22, (November 2007), pp.7665- 7675,

No.6, (June 2001), pp.233-234, ISSN 1137-8498

pp. 525–527, ISSN 1045-9833

(June 1994), pp.203-210, ISSN 794- 8948

(March 2003), pp. 577-590. ISSN 1266-7443

2008), pp.213-226, ISSN 1841-1307

pp.9-15, ISSN 1503-3688

1950-2805

ISSN 2109-5589

ISSN 1798-2172

8434

No.1-2, (September 2005), pp.260– 274, ISSN 1592-1706


Liu, Z.M.; Chen, G.G.; Ng, E.K.; Leung, W.K.; Sung, J.J. & Chung, S.C. (2004). Upregulation

Lu, T.; Pan, Y.; Kao, S.Y.; Li, C.; Kohane, I.; Chan, J. & Yankner, B.A. (2004). Gene regulation

Lukas, C.; Bartkova, J.; Latella, L.; Falck, J.; Mailand, N.; Schroeder, T.; Sehested, M.; Lukas,

Luo, J.; Nikolaev, A.Y.; Imai, S.; Chen, D.; Su, F.; Shiloh, A.; Guarente, L. & Gu, W. (2001).

Macůrek, L.; Lindqvist, A.; Voets, O.; Kool, J.; Vos, H.R. & Medema, R.H. (2010). Wip1

Mahaney, B.L.; Meek, K. & Lees-Miller, S.P. (2009). Repair of ionizing radiation-induced

Mailand, N.; Bekker-Jensen,S.; Bartek, J. & Lukas, J. (2006). Destruction of Claspin by

Marchenko. N.D.; Zaika, A. & Moll, U.M. (2000) Death signal-induced localization of p53

Martin, L.J. (2008). DNA damage and repair: relevance to mechanisms of

Martin, L.J.; Liu, Z.; Pipino, J.; Chestnut, B. & Landek, M.A. (2009). Molecular regulation of

Martinez, L.A.; Yang, J.; Vazquez, E.S.; Rodriguez-Vargas Mdel, C.; Olive, M.; Hsieh, J.T.;

*Carcinogenesis*, Vol.23, No.8, (August 2002), pp.1289–1296, ISSN 1215-1346 Mazumder, S.; Plesca, D.; Kinter, M. & Almasan, A. (2007). Interaction of a cyclin e fragment

Vol.275, No.21, (May 2000), pp.16202–16212, ISSN 1082-1866

Vol.19, No.6, (September 2008), pp. 1273-1293, ISSN 1882-0287

stress. *Mol Cell,* Vol.23, No.3, (August 2006), pp.307–318, ISSN 1688-5021 Mamely, I., van Vugt, M.A., Smits, V.A., Semple, J.I., Lemmens, B., Perrakis, A., Medema,

pp.861–869, ISSN 1794-3134

pp.883-891, ISSN 1519-0254

2291, ISSN 2010-1220

ISSN 1843-1258

No.13, (July 2001), pp.4990-4903, ISSN 1143-1331

No.3, (February 2009), pp.639–650, ISSN 1913-3841

(August 2006), pp. 1950-1955, ISSN 1693-4469

2007), pp.3511-3520, ISSN 1732-5036

Vol.107, No.2, (October 2001), pp. 137-148, ISSN 1167-2522

of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells. *Oncogene*, Vol.23, No.2, (January 2004), pp.503-13, ISSN 1464-7439 Lobrich, M. & Jeggo, P.A. (2007). The impact of a negligent G2/M checkpoint on genomic

instability and cancer induction. *Nat Rev Cancer*, Vol. 7, No.11, (November 2007),

and DNA damage in the ageing human brain. *Nature*, Vol.429, No.6994, (June 2004),

J. & Bartek, J. (2001). DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. *Cancer Res*, Vol.61,

Negative control of p53 by Sir2alpha promotes cell survival under stress. *Cell*,

phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition. *Oncogene*, Vol.29, No.15, (January 2010), pp.2281-

DNA double-strand breaks by non- homologous end-joining. *Biochem,* Vol.417,

SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic

R.H, & Freire, R. (2006). Pololike kinase-1 controls proteasome-dependent degradation of claspin during checkpoint recovery. *Curr Biol*, Vol.16, No.19,

protein to mitochondria. A potential role in apoptotic signaling. *J Biol Chem*,

neurodegeneration. *J Neuropathol Exp Neurol*, Vol.67, No.5, (May 2008), pp.377-387,

DNA damage-induced apoptosis of neurons in cerebral cortex. *Cerebral Cortex*,

Logothetis, C.J. & Navone, N.M. (2002).p21 modulates threshold of apoptosis induced by DNA-damage and growth factor withdrawal in prostate cancer cells.

with Ku70 regulates bax- mediated apoptosis. *Mol Cell Biol*, Vol.27, No.9, (February


Cell Cycle and DNA Damage Response in Postmitotic Neurons 273

Oku, T.; Ikeda, S.; Sasaki, H.; Fukuda, K.; Morioka, H.; Ohtsuka, E.; Yoshikawa, H. &

Otsuka, Y.; Tanaka, T.; Uchida, D.; Noguchi, Y.; Saeki, N.; Saito, Y. & Tatsuno, I. (2004).

Pajalunga, D.; Mazzola, A.; Salzano, A.M.; Biferi, M.G.; De Luca, G. & Crescenzi, M. (2007).

Pardo, B.; Gómez-González, B. & Aguilera, A. (2009). DNA repair in mammalian cells: DNA

Park, D.S.; Morris, E.J.; Greene, L.A. & Geller, H.M. (1997). G1/S cell cycle blockers and

agents. *J Cell Biol*, Vol.143, No.2, (October 1998), pp.457–467, ISSN 978-6955 Perry, J.J.; Yannone, S.M.; Holden, L.G.; Hitomi, C.; Asaithamby, A.; Han, S.; Cooper, P.K.;

Peterson, C.L. & Cote, J. (2004) Cellular machineries for chromosomal DNA repair. *Genes* 

Phillips, A.C. & Vousden, K.H. (2001). E2F-1 induced apoptosis. *Apoptosis*, Vol.6, No.3, (June

Pickart, C.M. (2001). Ubiquitin enters the new millennium. *Mol Cell*, Vol.8, No.3, (September

Picard, F.; Kurtev, M.; Chung, N.; Topark-Ngarm, A.; Senawong, T.; Machado De Oliveira,

Poehlmann, A. & Roessner, A. (2010). Importance of DNA damage checkpoints in the

Polager, S. & Ginsberg, D. (2008). E2F – at the crossroads of life and death. *Trends Cell Biol*,

Polager, S. & Ginsberg, D. (2009). p53 and E2f: partners in life and death. *Nat Rev Cancer*,

Polo, S.E.; Kaidi, A.; Baskcomb, L.; Galanty, Y.& Jackson, S.P. (2010). Regulation of DNA-

CHD4. *EMBO J*, Vol.29, No.18, (August 2010), pp.3130-3139, ISSN 2069-3977

Vol.18, No.11, (September 2008), pp. 528-535, ISSN 1880-5009

Vol.9, No.10, (October 2009), pp.738-748, ISSN 1977-6743

R.; Leid, M.; McBurney, M.W. & Guarente, L. (2004). Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. *Nature,* Vol.429,

pathogenesis of human cancers. *Pathol Res Pract*, Vol.206, No.9, (August 2010), pp.

damage responses and cell-cycle progression by the chromatin remodelling factor

*Cell Biol*, Vol.176, No.6, (March 2007), pp.1039-1056, ISSN 1735-3358

Vol.66, No.6, (March 2009), pp.1039-1056, ISSN 1915-3654

Vol.13, No.5, (April 2006), pp.414-422. ISSN 1662-2405

No.6993, (June 2004), pp. 771-776, ISSN 1517-5761

2001), pp.173–182. ISSN 1138- 8666

2001), pp.499-504. ISSN 1158- 3613

591-601, ISSN 2067-4189

*Dev*, Vol.18, No.6, (March 2004), pp.602-616. ISSN 1507-5289

No.6, (June 1998), pp. 357-369, ISSN 973-4782

(July 2004), pp. 180-185, ISSN 1524-6544

Tsurimoto, T. (1998). Functional sites of human PCNA which interact with p21 (Cip1/Waf1), DNA polymerase delta and replication factor C. *Gene Cells*, Vol.3,

Roles of cyclin-dependent kinase 4 and p53 in neuronal cell death induced by doxorubicin on cerebellar granule neurons in mouse. *Neurosci Lett*, Vol.365, No.3,

Critical requirement for cell cycle inhibitors in sustaining nonproliferative states. *J* 

double-strand break repair: how to fix a broken relationship. *Cell Mol Life Sci*,

inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis. *J Neurosci*, Vol.17, No.4, (February 1997), pp. 1256–1270, ISSN 900- 6970 Park, D.S.; Morris, E.J.; Padmanabhan, J.; Shelanski, M.L.; Geller, H.M. & Greene, L.A. (1998).

Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging

Chen, D.J. & Tainer, J.A. (2006). WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing. *Nat Struct Mol Biol*,


Murr, R.; Loizou, J.I.; Yang, Y.G.; Cuenin, C.; Li, H.; Wang, Z.Q. & Herceg, Z. (2006). Histone

Nagayama, T.; Lan, J.; Henshall, D.C.; Chen, D.; O'Horo, C.; Simon, R.P. & Chen, J. (2000).

Nakada, S.; Chen, G.I.; Gingras, A.C. & Durocher, D. (2008). PP4 is a gamma H2AX

Nakamura, T.M.; Du, L.L.; Redon, C. & Russell, P. (2004). Histone H2A phosphorylation

Narciso, L.; Fortini, P.; Pajalunga, D.; Franchitto, A.; Liu, P.; Degan, P.; Frechet, M.; Demple,

Nicassio, F.; Corrado, N.; Vissers, J.H.; Areces, L.B.; Bergink, S.; Marteijn, J.A.; Geverts, B.;

*Curr Biol*, Vol.17, No.22, (November 2007), pp.1972-1977, ISSN 1798-0597 Nouspikel, T. & Hanawalt, P.C. (2000). Terminally differentiatedhuman neurons repair

Nouspikel, T. & Hanawalt, P.C. (2002). DNA repair in terminally differentiated cells. *DNA* 

Nouspikel, T. (2007). DNA repair in differentiated cells: some new answers to old questions. *Neuroscience,* Vol.145, No.4, (August 2006), pp.1213-1221, ISSN 1692-0273 Oberdoerffer, P.; Michan, S.; McVay, M.; Mostoslavsky, R.; Vann, J.; Park, S.K.; Hartlerode,

*Repair (Amst),* Vol.1, No.1, (January 2002), pp.59-75, ISSN 1250-9297

Vol.275, No.33, (August 2000), pp. 25358–25364, ISSN 1085- 1232

*Chem*, Vol.283, No.7, (December 2007), pp. 3979-3987, ISSN 1805-6705

Vol.9, No.10, (August 2008), pp.1019-1026, ISSN 1875-8438

1205

1098-7855

1066-9734

pp.6215-6230, ISSN 1522-6425

acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. *Nat Cell Biol,* Vol.8, No.1, (Dec 2006), pp.91–99, ISSN 1634-

Induction of oxidative DNA damage in the peri-infarct region after permanent focal cerebral ischemia. *J Neurochem*, Vol.75, No.4, (October 2000), pp.1716-1728, ISSN

phosphatase required for recovery from the DNA damage checkpoint. *EMBO Rep*,

controls Crb2 recruitment at DNA breaks, maintains checkpoint arrest, and influences DNA repair in fission yeast. *Mol Cell Biol*, Vol.24, No.1,14, (July 2004),

B.; Crescenzi, M. & Dogliotti, E. (2007). Terminally differentiated muscle cells are defective in base excision DNA repair and hypersensitive to oxygen injury. *Proc Natl Acad Sci U S A*, Vol.104, No.43, (October 2007), pp.17010-17015, ISSN 1794-0040

Houtsmuller, A.B.; Vermeulen, W.; Di Fiore, P.P. & Citterio, E. (2007). Human USP3 is a chromatin modifier required for S phase progression and genome stability.

transcribed genes but display attenuated global DNA repair and modulation of repair gene expression.*Mol Cell Biol*, Vol.20, No.5, (March 2000), pp.1562–1570, ISSN

A.; Stegmuller, J.; Hafner, A.; Loerch, P.; Wright, S.M.; Mills, K.D.; Bonni, A.; Yankner, B.A.; Scully, R.; Prolla, T.A.; Alt, F.W. & Sinclair, D.A. (2008). SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. *Cell*, Vol.135, No.5, (November 2008), pp.907-918, ISSN 1904-1753 O'Hagan, H.M.; Mohammad, H.P. & Baylin, S.B. (2008). Double strand breaks can initiate gene

silencing and SIRT1- dependent onset of DNA methylation in an exogenous promoter CpG island. *PLoS Genet*, Vol.4, No.8, (August 2008), pp.e1000155, ISSN 1870-4159 O'Hare, M.J.; Hou, S.T.; Morris, E.J.; Cregan, S.P.; Xu, Q.; Slack, R.S. & Park, D.S. (2000).

Induction and modulation of cerebellar granule neuron death by E2F-1. *J Biol Chem*,

Nakagawara, A. & Kizaki, H. (2008). Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. *J Biol* 

Okoshi, R.; Ozaki, T.; Yamamoto, H.; Ando, K.; Koida, N.; Ono, S.; Koda, T.; Kamijo, T.;


Cell Cycle and DNA Damage Response in Postmitotic Neurons 275

Sancar, A.; Lindsey-Boltz, L.A.; Unsal-Kacmaz, K. & Linn, S. (July 2004). Molecular

Schlereth, K.; Beinoraviciute-Kellner, R.; Zeitlinger, M.K.; Bretz, A.C.; Sauer, M.; Charles,

Schmetsdorf, S.; Gartner, U. & Arendt, T. (2007). Constitutive expression of functionally

Schmetsdorf, S.; Arnold, E.; Holzer, M.; Arendt, T.& Gartner, U. (2009). A putative role for

Schuler, M.; Bossy-Wetzel, E.; Goldstein, J.C.; Fitzgerald, P. & Green, D,R. (2000) p53 induces

Shanbhag, N.M.; Rafalska-Metcalf, I.U.; Balane-Bolivar, C.; Janicki, S.M. & Greenberg, R.A.

Shao, G.; Lilli, D.R.; Patterson-Fortin, J.; Coleman, K.A.; Morrissey, D.E. & Greenberg, R.A.

Sharma, G.; Mirza, S.; Parshad, R.; Srivastava, A.; Gupta, S.D.; Pandya, P. & Ralhan, R.

Shieh, S-Y.; Ikeda, M.; Taya, Y. & Prives, C. (1997). DNA damage-induced phosphorylation

Shieh, S.Y.; Ahn, J.; Tamai, K.; Taya, Y. & Prives, C. (2000). The human homologs of

*Chem*, Vol.275, No.10, (March 2000), pp. 7337-7342, ISSN 1070-2305

*Rev Biochem, Vol.* 73, No. , (January, 2004), pp.39–85, ISSN 1518-9136 Sanders, S.L.; Arida, A.R. & Phan, F.P. (2010). Requirement for the phospho-H2AX binding

*Cell Biol*, Vol.30, N0.19, (August 2010), pp.4722-4731, ISSN 2067-9488 Sartori, A.A.; Lukas, C.; Coates, J.; Mistrik, M.; Fu, S.; Bartek, J.; Baer, R.; Lukas, J. & Jackson,

(October 2007), pp.509–514, ISSN 1796-5729

No.8, (October 2006), pp.1821–1829, ISSN 1705-0646

Vol.29, No.6, (March 2009), pp.1096–10107, ISSN 1930-2146

*Bull,* Vol.73, No1-3, (June 2007), pp.48–54. ISSN 1749-9636

Vol.87, No.3-4, (May 2010), pp.83-91, ISSN 2047-0789

9744-860

368, ISSN 2047-1942

334, ISSN 936-3941

ISSN 1067-3501

acetylation cascade. *Genes Dev*, Vol.12, N0.18, (September 1998), pp.2831-2841, ISSN

mechanisms of mammalian DNA repair and the DNA damage checkpoints. *Annu* 

module of Crb2 in double-strand break targeting and checkpoint activation. *Mol* 

S.P. (2007). Human CtIP promotes DNA end resection. Nature, Vol.450, No.7169,

J.P.; Vogiatzi, F.; Leich, E.; Samans, B.; Eilers, M.; Kisker, C.; Rosenwald, A. & Stiewe, T. (2010). DNA binding cooperativity of p53 modulates the decision between cell cycle arrest and apoptosis. *Mol Cell*, Vol.38, No.3, (May 2010), pp.356-

active cyclin dependent kinases and their binding partners suggests noncanonical functions of cell cycle regulators in differentiated neurons. *Cereb Cortex,* Vol.17,

cell cycle-related proteins in microtubule-based neuroplasticity. *Eur J Neurosci* ,

apoptosis by caspase activation through mitochondrial cytochrome c release. *J Biol* 

(2010). ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. *Cell*, Vol.1413, No.6, (June 2010), pp.970– 981. ISSN 2055-0933

(2009). The Rap80-BRCC36 de- ubiquitinating enzyme complex antagonizes RNF8- Ubc13-dependent ubiquitination events at DNA double strand breaks. *Proc Natl Acad Sci U S A*, Vol.106, No.9, (February 2009), pp. 3166-3171, ISSN 1920-2061 Sharma, S. (2007). Age-related nonhomologous end joining activity in rat neurons. *Brain Res* 

(2010). Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients. *Life Sci*,

of p53 alleviates inhibition by MDM2. *Cell*, Vol.91, No.3, (October, 2003), pp. 325-

checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. *Genes Dev*, Vol.14, No.3, (February, 2000), pp. 289- 300,


Polo, S.E. & Jackson, S.P. (2011). Dynamics of DNA damage response proteins at DNA

Qin, S. & Parthun, M.R. (2006). Recruitment of the type B histone acetyltransferase Hat1p to

Rass, U.; Ahel, I. & West, S.C. (2007). Defective DNA repair and neurodegenerative disease.

Reagan-Shaw, S. & Ahmad, N. (2005). Silencing of polo-like kinase (Plk) 1 via siRNA causes

Reed, J.C. (2006). Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms,

Reinhardt, H.C. & Yaffe, M.B. (2009). Kinases that control the cell cycle in response to DNA

Rich, T.; Allen, R.L. & Wyllie, A.H. (2000). Defying death after DNA damage. *Nature*,

Riley, T.; Sontag, E.; Chen, P. & Levine, A. (2008). Transcriptional control of human p53-

Rinaldo, C.; Prodosmo, A.; Mancini, F.; Iacovelli, S.; Sacchi, A.; Moretti, F. & Soddu, S.

Rogakou, E.P.; Pilch, D.R.; Orr, A.H.; Ivanova, V.S. & Bonner, W.M. (1998). DNA double-

Rolig, R.L. & McKinnon, P.J. (2000). Linking DNA damage and neurodegeneration. *Trends Neuroscie*, Vol*.*23, No.9, (September 2000), pp. 417-424, ISSN 1094-1191 Roshak, A.K.; Capper, E.A.; Imburgia, C.; Fornwald, J.; Scott, G. & Marshall, L.A. (2000). The

Rossi, M.; De Laurenzi, V.; Munarriz, E.; Green, D.R.; Liu, Y.C.; Vousden, K.H.; Cesareni, G.

Rouse, J. & Jackson SP. (2002). Interfaces between the detection, signaling, and repair of DNA damage. *Science,* Vol*.*297, No.5581, (July, 2002), pp. 547–551, ISSN 1214-2523] Sakaguchi, K.; Herrera, J.E.; Saito, S.; Miki, T.; Bustin, M.; Vassilev, A.; Anderson, C.W. &

*J*, Vol.24, No.4, (February 2005), pp. 836–848, ISSN 1567- 8106

1998 Mar 6;Vol.273, No.10, (March 1998), pp.5858-5868, ISSN 9488723 Rogoff, H.A. & Kowalik, T.F. (2004). Life, death and E2F: linking proliferation control and

Vol.407, No.6805, (October 2000), pp.777–783, ISSN 1104-8728

*Cell,* Vol.130, No.6, (September 2007), pp.991-1004, ISSN 1788-9645

pp.409-33, ISSN 2136-3960

2006), pp.3649-3658, ISSN 1661-2003

No.6, (January 2005), pp.611-613, ISSN 1566-1849

(June 2006), pp.1378-1386, ISSN 1672-9025

pp.245–255, ISSN 1923-0643

1843-1400

750, ISSN 1734-9959

ISSN 1519-0206

411, ISSN 1120-2906

breaks: a focus on protein modifications. *Genes Dev*, Vol.25, No.5, (March, 2011),

chromatin is linked to DNA double-strand breaks. *Mol Cell Biol*, Vol.26, No.9, (May

induction of apoptosis and impairment of mitosis machinery in human prostate cancer cells: implications for the treatment of prostate cancer. *FASEB J*, Vol.19,

physiological roles and therapeutic opportunities. *Cell Death Differ*, Vol.13, No.8,

damage: Chk1, Chk2, and MK2. *Curr Opin Cell Biol,* Vol.21, No.2, (February 2009),

regulated genes. *Nat Rev Mol Cell Biol*, Vol.9, No.5, (May 2008), pp.402-412, ISSN

(2007). MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis. *Mol Cell*, Vol.25, No.5, (March 2007), pp.739-

stranded breaks induce histone H2AX phosphorylation on serine 139. *J Biol Chem*,

DNA damage signaling via E2F1. *Cell Cycle*, Vol*.*3, No.7, (July 2004), pp. 845–846,

human polo-like kinase PLK, regulates cdc2/cyclin B through phosphorylation and activation of the cdc25C phosphatase, *Cell Signal*, Vol*.*12, No.6, (June 2000), pp. 405–

& Melino, G. (2005) The ubiquitin-protein ligase Itch regulates p73 stability. *EMBO* 

Appella, E. (1998). DNA damage activates p53 through a phosphorylation-

acetylation cascade. *Genes Dev*, Vol.12, N0.18, (September 1998), pp.2831-2841, ISSN 9744-860


Cell Cycle and DNA Damage Response in Postmitotic Neurons 277

Stiff, T.; O'Driscoll, M.; Rief, N.; Iwabuchi, K.; Löbrich, M. & Jeggo, P.A. (2004). ATM and

Stucki, M.; Clapperton, J.A.; Mohammad, D.; Yaffe, M.B.; Smerdon, S.J. & Jackson SP. (2005).

Subramanian, C.; Opipari, A.W. Jr.; Bian, X.; Castle, V.P. & Kwok, R.P. (2005). Ku70

Suzuki, A.; Tsutomi, Y.; Akahane, K.; Araki, T. & Miura, M. (1998). Resistance to Fas-

Suzuki, A.; Tsutomi, Y.; Miura, M. & Akahane, K. (1999). Caspase 3 inactivation to suppress

Sykes, S.M.; Mellert, H.S.; Holbert, M.A.; Li, K.; Marmorstein, R.; Lane, W.S. & McMahon,

Tanaka, T.; Ohkubo, S.; Tatsuno, I. & Prives, C. (2007). hCAS/CSE1L associates with

Tang, Y.; Luo, J.; Zhang, W. & Gu, W. (2006). Tip60-dependent acetylation of p53 modulates

Tamburini, B.A. & Tyler, J.K. (2005). Localized histone acetylation and deacetylation triggered

Tibbetts, R.S.; Brumbaugh, K.M.; Williams, J.M.; Sarkaria, J.N.; Cliby, W.A.; Shieh, S.Y.;

Timinszky, G.; Till, S.; Hassa, P.O.; Hothorn, M.; Kustatscher, G.; Nijmeijer, B.; Colombelli,

*Biol*, 2005 Jun;Vol.25, No.12, (June 2005), pp.4903-4913, ISSN 1592-3609 Taylor, W.R. & Stark, G.R. (2001). Regulation of the G2/M transition by p53. *Oncogene*,

Vol.20, No.15, (April 2001), pp.1803– 1815, ISSN1131-3928

*Mol Cell* Vol.31, No.1, (July 2008), pp.21-32, ISSN 1861-4044

ISSN 1637-7563

ISSN 1577-8293

939, ISSN 974-7872

1244, ISSN 1002-2130

pp.10253–10257, ISSN 1707-9442

pp. 152-157, ISSN 992-5639

(August 2007), pp.638-650, ISSN 1771-9542

(December 2006), pp.827-839, ISSN 1718-9186

DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. *Cancer Res*, Vol.64, No.7, (April 2004), pp.2390-2396, ISSN 1505-9890 Stracker, T.H.; Couto, S.S.; Cordon-Cardo, C.; Matos, T. & Petrini, J.H. (2008). Chk2

suppresses the oncogenic potential of DNA replication-associated DNA damage.

MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. *Cell*, Vol.123, No.7, (December 2005), pp.1213–1226,

acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. *Proc Natl Acad SciUSA*, Vol.102, No.13, (March 2005), pp. 4842-4847,

mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP. *Oncogene*, Vol.17, No.8, (August 1998), pp. 931-

Fas-mediated apoptosis: identification of binding domain with p21 and ILP and inactivation machinery by p21. *Oncogene*, Vol.18, No.5, (February 1999), pp. 1239-

S.B. (2006). Acetylation of the p53 DNA-binding domain regulates apoptosis induction. *Mol Cell*, Vol.24, No.6, (December 2006), pp.841-851, ISSN 1718- 9187 Syljuasen, R.G.; Jensen, S.; Bartek, J. & Lukas, J. (2006) Adaptation to the ionizing radiation-

induced G2 checkpoint occurs in human cells and depends on checkpoint kinase 1 and Polo-like kinase 1 kinases. *Cancer Res*, Vol.66, No.21, (November 2006),

chromatin and regulates expression of select p53 target genes. *Cell*, Vol.130, No.4,

the decision between cell cycle arrest and apoptosis. *Mol Cell*, Vol.24, No.6,

by the homologous recombination pathway of double-strand DNA repair. *Mol Cell* 

Taya, Y.; Prives, C. & Abraham, R.T. (1999). A role for ATR in the DNA damageinduced phosphorylation of p53. *Genes Dev*, Vol.13, No.2, (January 1999),

J.; Altmeyer, M.; Stelzer, E.H.; Scheffzek, K.; Hottiger, M.O. & Ladurner, A.G.


Shiloh, Y. (2003). ATM and related protein kinases: safeguarding genome integrity. *Nat Rev* 

Shiloh, Y. (2006). The ATM-mediated DNA-damage response: taking shape. *Trends Biochem* 

Singleton, B.K.; Torres-Arzayus, M.I.; Rottinghaus, S.T.; Taccioli, G.E. & Jeggo, P.A. (1999).

Smerdon MJ, Tlsty TD, Lieberman MW. (1978). Distribution of ultraviolet-induced DNA

Smith, D.S.; Leone, G.; DeGregori, J.; Ahmed, M.N.; Qumsiyeh, M.B. & Nevins, J.R. (2000).

Sofueva S, Du LL, Limbo O, Williams JS, Russell P. (2010). BRCT domain interactions with

Sordet, O.; Redon, C.E.; Guirouilh-Barbat, J.; Smith, S.; Solier, S.; Douarre, C.; Conti, C.;

Soutoglou, E. & Misteli, T. (2008). Activation of the cellular DNA damage response in the

Spycher, C.; Miller, E.S.; Townsend, K.; Pavic, L.; Morrice, N.A.; Janscak, P.; Stewart, G.S. &

Stark, G.R. & Taylor, W.R. (2006). Control of the G2/M transition. *Mol. Biotechnol*, Vol.32,

Steelman, L.S. & McCubrey, J.A. (2010). Intriguing novel abilities of Nutlin-3A: induction of

Stewart, G.S.; Wang, B.; Bignell, C.R.; Taylor, A.M. & Elledge, S.J. (2003). MDC1 is a

Stewart, N.; Hicks, G.G.; Paraskevas, F. & Mowat, M. (1995). Evidence for a second cell cycle

*Biochemistry*, Vol.17, No.12, (June 1978), pp.2377–2386, ISSN 678515

The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit. *Mol Cell Biol*, Vol.19, No.15, (May 1999), pp. 3267-3277, ISSN1020- 7052 Sinha, S.; Malonia, S.K.; Mittal, S.P.; Singh, K.; Kadreppa, S.; Kamat, R.; Mukhopadhyaya, R.;

Pal, J.K. & Chattopadhyay, S. (2010). Coordinated regulation of p53 apoptotic targets Bax and Puma by SMAR1 through an identical MAR element. *EMBO J*,

repair synthesis in nuclease sensitive and resistant regions of human chromatin.

Induction of DNA replication in adult rat neurons by deregulation of the retinoblastoma/E2F G1 cell cycle pathway. *Cell Growth Differ*, Vol.11, No.12,

phospho-histone H2A target Crb2 to chromatin at double-strand breaks and maintain the DNA damage checkpoint. *Mol Cell Biol*, Vol.30, No.19, (August 2010),

Nakamura, A.J.; Das, B.B.; Nicolas, E.; Kohn, K.; Bonner, W.M. & Pommier, Y. (2009). Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks. *EMBO Rep*, Vol.10, No.8,

absence of DNA lesions. *Science*, Vol.320, No.5882, (May 2008), pp.1507-1510, ISSN

Stucki, M. (2008). Constitutive phosphorylation of MDC1 physically links the MRE11-RAD50-NBS1 complex to damaged chromatin. *J Cell Biol*, Vol.181, No.2,

cellular quiescence as opposed to cellular senescence - implications for chemotherapy. *Cell Cycle*, Vol.8, No.22, (November 2010), pp. 3634-3635, ISSN 1987-

mediator of the mammalian DNA damage checkpoint. *Nature*, Vol.421, No.6926,

block at G2/M by p53. *Oncogene*, Vol. 10, No.1, (January 1995), pp. 109-115, ISSN

*Cancer,* 2003; Vol.3, No.3, (March, 2003), pp.155-168, ISSN 1261-2651

*Sci,* Vol.31, No.7 (June 2006), pp.402-10. ISSN 1677-4833

Vol.29, No.4, (January 2010), pp.830-842, ISSN 2007-5864

(December 2000), pp. 625-633, ISSN 1114-9597

pp.4732-4743, ISSN 2067-9485

1848-3401

5921

7529-916

(June 2009), pp.887-893, ISSN 1955-7000

(April 2008), pp.227-240, ISSN 1841-1308

No.3, (March 2006), pp.227-248, ISSN 1663-2889

(February 2003), pp. 961–966, ISSN1260-7005


Cell Cycle and DNA Damage Response in Postmitotic Neurons 279

Vaseva, A.V.; Marchenko, N.D. & Moll, U.M. (2009). The transcription-independent

Vaziri, H.; Dessain, S.K.; Ng Eaton, E.; Imai, S.;, Frye, R.A.; Pandita, T.K.; Guarente, L. &

deacetylase. *Cell*, Vol.107, No.2, (October 2001), pp. 149-159, ISSN 1167-2523 Waldman, T.; Lengauer, C.; Kinzler, K.W. & Vogelstein, B. (1996). Uncoupling of S phase

Waldman, T.; Zhang, Y.; Dillehay, L.; Yu, J.; Kinzler, K.; Vogelstein, B. & Williams, J. (1997).

Wang, M.; Wu, W.; Wu, W.; Rosidi,B.; Zhang,L.; Wang, H. & Iliakis, G. (2006). PARP-1 and Ku

Warbrick, E.; Lane, D.P.; Glover, D.M. & Cox, L.S. (1995). A small peptide inhibitor of DNA

Wefel, J.S.; Kayl, A.E. & Meyers, C.A. (2004). Neuropsychological dysfunction associated

Weissman, L.; de Souza-Pinto, N.C.; Stevnsner, T. & Bohr, V.A. (2007). DNA repair,

Wilker, E.W.; van Vugt, M.A.; Artim, S.A.; Huang, P.H.; Petersen, C.P.; Reinhardt, H.C.;

Wilson, D. M. 3rd. & McNeill, D. R. (2007). Base excision repair and the central nervous system. *Neuroscience,* Vol.145, No.4 (August 2006), pp.1187–1200, ISSN 1693-4943 Xiong, Y.; Hannon, G.J.; Zhang, H.; Casso, D.; Kobayashi, R. & Beach, D. (1993). p21 is a

Xu Y, Sun Y, Jiang X, Ayrapetov MK, Moskwa P, Yang S, Weinstock DM, Price BD. (2010).

Yamaguchi, H.; Woods, N.T.; Piluso, L.G.; Lee, H.H.; Chen, J.; Bhalla, K.N.; Monteiro, A.;

*Cancer*, Vol. 90, No.9 (May, 2004), pp.1691-1696, ISSN 1515-0608

No.6584, (June 1996), pp.713-716, ISSN 864-9519

(September 1997), pp. 1034-1036, ISSN 928-8734

2001), pp.47759-47762, ISSN 1167-3449

(March 1995), pp.275-282, ISSN 778-0738

2006), pp.1318–1329, ISSN 1709-2652

2007), pp.329-332, ISSN 1736-1185

pp.701-704, ISSN 825-9214

2087-6283

ISSN 1219-1482

mitochondrial p53 program is a major contributor to nutlin-induced apoptosis in tumor cells. *Cell Cycle*, Vol.8, No.11, (June 2009), pp.1711-1719, ISSN 1941- 1846 Vaze, M.B.; Pellicioli, A.; Lee, S.E.; Ira, G.; Liberi, G.; Arbel-Eden, A.; Foiani, M. & Haber JE.

(2002) Recovery from checkpoint-mediated arrest after repair of a double-strand break requires Srs2 helicase. *Mol Cell*, Vol. 10, No.2, (August 2002), pp. 373–385,

Weinberg, R.A. (2001). hSIR2(SIRT1) functions as an NAD-dependent p53

and mitosis induced by anticancer agents in cells lacking p21. *Nature*, Vol.381,

*Cell cycle*, arrest versus cell death in cancer therapy. *Nat Med,* Vol.3, No.9,

compete for repair of DNA double strand breaks by distinct NHEJ pathways. *Nucleic Acids Res,* 2006;Vol.34, No.21, (November 2006), pp.6170- 6182, ISSN 1708-8286 Ward, I.M. & Chen, J. (2001). Histone H2AX is phosphorylated in an ATR-dependent

manner in response to replicational stress. *J Biol Chem*, Vol.276, No.51, (October

replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21WAF1 and proliferating cell nuclear antigen. *Curr Biol*, Vol.5, No.3,

with cancer and cancer therapies: a conceptual review of an emerging target. *Br J* 

mitochondria, and neurodegeneration. *Neuroscience*, Vol. 145, No.4 (November,

Feng, Y.; Sharp, P.A.; Sonenberg, N.; White, F.M. & Yaffe, M.B. (2007). 14-3-3sigma controls mitotic translation to facilitate cytokinesis. *Nature*, Vol.446, No.7133 (March

universal inhibitor of cyclin kinases. *Nature*, Vol.366, No.6456, (December 1993),

The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair. *J Cell Biol,* Vol.191, No.1, (September 2010), pp.31-43, ISSN

Liu, X.; Hung, M.C. & Wang, H.G. (2009). p53 acetylation is crucial for Its

(2009). A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. *Nat Struct Mol Biol*, Vol.16, No.9, (August 2009), pp.923-929, ISSN 1968-0243


Toczyski, D.P.; Galgoczy, D.J. & Hartwell, L.H. (1997) CDC5 and CKII control adaptation to

Tofilon, P.J. & Meyn, E. (1988). Reduction in DNA repair capacity following differentiation

Tomashevski, A.; Webster, D.R.; Grammas, P.; Gorospe, M. & Kruman, I.I. (2010). Cyclin-C-

Trushina, E. &C McMurray, C.T. (2007). Oxidative stress and mitochondrial dysfunction in

Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y. (2003). Requirement of

van Attikum, H.; Fritsch, O.; Hohn, B. & Gasser, S.M.( 2004). Recruitment of the INO80

van Attikum, H.; Fritsch, O. & Gasser, S.M. (2007). Distinct roles for SWR1 and INO80

Van Attikum, H. & Gasser, S.M. (2005) The histone code at DNA breaks: a guide to repair? *Nat Rev Mol Cell Biol*, Vol. 6, No.10, (October 2005), pp.757-765, ISSN 1616-7054 van Attikum, H. & Gasser, S.M. (2009). Crosstalk between histone modifications during the

van Gent, D.C. & van der Burg, M. (2007). Non-homologous end-joining, a sticky affair. *Oncogene*, Vol. 26, No.56, (December 2007), pp. 7731–7740, ISSN 1806-6085 van Vugt, M.A. & Medema, R.H. (2004). Checkpoint adaptation and recovery: back with

van Vugt, M.A.; Bras, A. & Medema, R.H. (2004). Polo-like kinase-1 controls recovery from a

van Vugt, M.A.; Gardino, A.K.; Linding, R.; Ostheimer, G.J.; Reinhardt, H.C.; Ong, S.E.; Tan,

Vol.26, No.18, (August 2007), pp.4113-4125. ISSN 1776-2868

ISSN 1968-0243

ISSN 333-8499

10106, ISSN 932-3137

1248, ISSN 1730-3344

788, ISSN 1560-7975

ISSN 1934-2239

1549-2511

6263

pp.1189-1198, ISSN 2011-1042

(October 2003), pp.5612-5621, ISSN 1453-2133

(September 2004), pp.799-811, ISSN 1535-0223

(2009). A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. *Nat Struct Mol Biol*, Vol.16, No.9, (August 2009), pp.923-929,

the yeast DNA damage checkpoint. *Cell*, Vol.90, No.6, (September 1997), pp.1097-

of murine proadipocytes. *Exp. Cell Res*, Vol.174, No.2, (February 1988), pp.502–510,

dependent cell-cycle entry is required for activation of non-homologous end joining DNA repair in postmitotic neurons. *Cell Death Differ*. Vol.17, No.7 (January 2010),

neurodegenerative diseases. *Neuroscience*, Vol.145, No.4 (February 2007), pp.1233–

the MRN complex for ATM activation by DNA damage. *EMBO J,* Vol.22, No20,

complex by H2A phosphorylation links ATP-dependent chromatin remodeling with DNA double-strand break repair. *Cell*, Vol.119, No.6,(December 2004), pp.777-

chromatin remodeling complexes at chromosomal double-strand breaks. *EMBO J*,

DNA damage response. *Trends Cell Biol*, Vol.19, No.5, (April 2009), pp.207-217,

Polo after the break. *Cell Cycle*, Vol.3, No.11, (November 2004), pp. 1383-1386, ISSN

G2 DNA damage-induced arrest in mammalian cells. *Mol Cell*, Vol. 15, No.5,

C.S.; Miao, H.; Keezer, S.M.; Li, J.; Pawson, T.; Lewis, T.A.; Carr, S.A.; Smerdon, S.J.; Brummelkamp, T.R. & Yaffe, M.B. (2010). A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G(2)/M DNA damage checkpoint. *PLoS Biol*, Vol. 8, No.1, (January 2010), pp.e1000287, ISSN 2012-


**1. Introduction** 

**15** 

*Poland* 

**TopBP1 in DNA Damage Response** 

Ewa Forma, Magdalena Brys and Wanda M. Krajewska

DNA, the genetic material of cells, is constantly exposed to a range of endogenous and environmental damaging agents (Jungmichel & Stucki, 2010). DNA molecule is the target of endogenous cellular metabolites such as reactive oxygen species (ROS) (Ciccia & Elledge, 2010; Poehlmann & Roessner, 2010). ROS may cause different alterations in a genome, e.g. simple DNA mutations, DNA single and double strand breaks (SSBs and DSBs, respectively), or more complex changes, including deletions, translocations and fusions (Poehlmann & Roessner, 2010). Alterations may be generated spontaneously due to dNTP misincorporation during DNA replication, interconversion between DNA bases caused by deamination, loss of DNA bases following DNA depurination or depyrimidination and modification of DNA bases by alkylation. Hydrolytic deamination (loss of an amino group) can directly convert one base to another. For example, deamination of cytosine results in uracil and with much lower frequency converts adenine to hypoxanthine. In depurination or depyrimidination, purine or pyrimidine bases are completely removed, leaving deoxyribose sugar depurinated or depyrimidinated that may cause breakage in the DNA backbone (Ciccia & Elledge, 2010; Rastogi et al., 2010). Altogether, it has been estimated that every cell could experience up to 105 spontaneous DNA lesions per day (Ciccia & Elledge, 2010). Environmental DNA damage can be produced by physical or chemical sources, such as ionizing radiation (IR), ultraviolet (UV) light from sunlight and organic and inorganic chemical substances (Muniandy et al., 2010; Rastogi et al., 2010; Su et al., 2010). Exposure to ionizing radiation from, e.g. cosmic radiation and medical treatments employing X-rays or radiotherapy inflicts DNA single and double strand breaks, oxidation of DNA bases and DNA-protein crosslinks in the genomic DNA (Ciccia & Elledge, 2010; Su et al., 2010). Ionizing radiation provokes DNA damage directly by energy deposit on the DNA double helix and indirectly by reactive oxygen/nitrogen species (ROS/RNS) (Corre et al., 2010). Ultraviolet radiation (mainly UV-B) is a powerful agent that may lead to the formation of three major classes of DNA lesions, such as cyclobutane pyrimidine dimmers (CPDs), pyrimidine 6-4 pyrimidone photoproducts (6-4 PPs) and their Devar isomers (Rastogi et al., 2010). Cells may become transiently exposed to external sources of DNA damage, such as cigarette smoke or various toxic chemical compounds (Jungmichel & Stucki, 2010). Many antineoplastic drugs currently used in cancer treatment express their cytotoxic effects through their ability to directly or indirectly damage DNA and thus resulting in cell death. Major types of DNA damage induced by anticancer treatment include single and double strand breaks, interstrand, intrastrand and DNA-protein crosslinks, as well as interference

*Department of Cytobiochemistry, University of Lodz* 

transcription-independentproapoptotic functions. *J Biol Chem*, Vol.284, No.17, (March 2009), pp. 11171-11183, ISSN 1926-5193

