**7. Conclusions**

A large body of work has been focused on identifying the mechanisms that regulate E2F activity and its consequences on induction of DNA repair. As a result, it has become apparent that E2F activity is complex, and is regulated at multiple levels, including transcription, post-translational modifications and protein-protein interactions. However, understanding of how different post-translational modifications modulate E2F interactions with other proteins, allowing it to form transcriptional activator or repressor complexes is in its infancy.

The biological roles of the various modes of E2F modulation go well beyond normal development and cell differentiation, implicate mechanisms of DNA repair as a central function, and are involved in the genesis of multiple pathologies.

Although pRb family proteins form the central backbone of E2F regulation, they are only one component. Studies of HPV proteins have shown that, in addition to E7, the proteins E5 and E6 are critical for the functional transformation of a cell. In the case of HPV, these proteins serve to deactivate the p53 pathway, preventing the pro-apoptotic responses normally switched on with abnormal activation of E2F. Other viruses encode proteins that serve a similar function. The identification and study of these proteins may provide key insights into the function of these viruses and the pathways that regulate E2F during normal tissue development and homeostasis, and affect DNA repair mechanisms to ensure viral replication.

#### **8. Acknowledgement**

Work in the author's laboratory was supported with funds from the Canadian Institutes of Health Research.

### **9. References**


transcriptional repression of genes necessary for the G2/M transition. Thus, B19V targets cells for arrest in the G2 phase by altering E2F activity, indicating the importance of this family of transcription factors in all phases of the cell cycle and multiple aspects of cell cycle

A large body of work has been focused on identifying the mechanisms that regulate E2F activity and its consequences on induction of DNA repair. As a result, it has become apparent that E2F activity is complex, and is regulated at multiple levels, including transcription, post-translational modifications and protein-protein interactions. However, understanding of how different post-translational modifications modulate E2F interactions with other proteins, allowing it to form transcriptional activator or repressor complexes is in

The biological roles of the various modes of E2F modulation go well beyond normal development and cell differentiation, implicate mechanisms of DNA repair as a central

Although pRb family proteins form the central backbone of E2F regulation, they are only one component. Studies of HPV proteins have shown that, in addition to E7, the proteins E5 and E6 are critical for the functional transformation of a cell. In the case of HPV, these proteins serve to deactivate the p53 pathway, preventing the pro-apoptotic responses normally switched on with abnormal activation of E2F. Other viruses encode proteins that serve a similar function. The identification and study of these proteins may provide key insights into the function of these viruses and the pathways that regulate E2F during normal tissue development and homeostasis, and affect DNA repair mechanisms to ensure

Work in the author's laboratory was supported with funds from the Canadian Institutes of

Almeida, M.I., Reis, R.M., and Calin, G.A. (2011). MicroRNA history: Discovery, recent

Bagchi, S., Raychaudhuri, P., and Nevins, J.R. (1989). Phosphorylation-dependent activation

Bennett, D., and Itoh, T. (2008). The XPE gene of xeroderma pigmentosum, its product and

Berkovich, E., and Ginsberg, D. (2003). ATM is a target for positive regulation by E2F-1.

Bernat, A., Avvakumov, N., Mymryk, J.S., and Banks, L. (2003). Interaction between the

of the adenovirus-inducible E2F transcription factor in a cell-free system. *Proc Natl* 

HPV E7 oncoprotein and the transcriptional coactivator p300. *Oncogene* 22,

function, and are involved in the genesis of multiple pathologies.

applications, and next frontiers. *Mutat Res*.

biological roles. *Adv Exp Med Biol* 63757-64).

*Acad Sci U S A* 86, 12.(4352-4356).

*Oncogene* 22, 2.(161-167).

39.(7871-7881).

progression and DNA replication and repair.

**7. Conclusions** 

its infancy.

viral replication.

Health Research.

**9. References** 

**8. Acknowledgement** 


Post-Transcriptional Regulation of E2F Transcription Factors: Fine-Tuning

issue.(D109-111).

*Nucleic Acids Res*.

fate. *Cell Cycle* 8, 4.(532-535).

Drosophila. *BMC Genet* 49).

93, 21.(11510-11515).

*Biol* 15, 6.(3082-3089).

*Genes Dev* 10, 23.(2949-2959).

*Dev* 3, 7.(1062-1074).

10, 23.(2960-2970).

8.(5027-5035).

DNA Repair, Cell Cycle Progression and Survival in Development & Disease 177

Giangrande, P., Zhu, W., Rempel, R. E., Laasko, N., and Nevins, J.R. (2004). Combinatorial gene control involving E2F and E box family members. *EMBO J* 231336-1347). Ginsberg, D., Vairo, G., Chittenden, T., Xiao, Z.X., Xu, G., Wydner, K.L., DeCaprio, J.A.,

transcription factor family, interacts with p107. *Genes Dev* 8, 22.(2665-2679). Griffiths-Jones, S. (2004). The microRNA Registry. *Nucleic Acids Res* 32, Database

Guo, J., Longshore, S., Nair, R., and Warner, B.W. (2009). Retinoblastoma protein (pRb), but

Guo, R., Chen, J., Mitchell, D.L., and Johnson, D.G. (2010a). GCN5 and E2F1 stimulate

Guo, R., Chen, J., Zhu, F., Biswas, A.K., Berton, T.R., Mitchell, D.L., and Johnson, D.G.

Halazonetis, T.D., Gorgoulis, V.G., and Bartek, J. (2008). An oncogene-induced DNA damage model for cancer development. *Science* 319, 5868.(1352-1355). Hallstrom, T.C., and Nevins, J.R. (2009). Balancing the decision of cell proliferation and cell

Hardy, S., Engel, D.A., and Shenk, T. (1989). An adenovirus early region 4 gene product is

Hateboer, G., Kerkhoven, R.M., Shvarts, A., Bernards, R., and Beijersbergen, R.L. (1996).

Helin, K., and Harlow, E. (1994). Heterodimerization of the transcription factors E2F-1 and

Heriche, J.K., Ang, D., Bier, E., and O'Farrell, P.H. (2003). Involvement of an SCFSlmb

Herrera, R.E., Chen, F., and Weinberg, R.A. (1996). Increased histone H1 phosphorylation

Hijmans, E.M., Voorhoeve, P.M., Beijersbergen, R.L., van 't Veer, L.J., and Bernards, R.

Hofmann, F., Martelli, F., Livingston, D.M., and Wang, Z. (1996). The retinoblastoma gene

Hsu, S.I.-H., Yang, C.M., Sim, K.G., Hentschel, D.M., O'Leary, E., and Bonventre, J.V. (2001).

differentiation in small intestine. *J Biol Chem* 284, 1.(134-140).

excision repair. *J Biol Chem* 285, 25.(19308-19315).

Lawrence, J.B., and Livingston, D.M. (1994). E2F-4, a new member of the E2F

not p107 or p130, is required for maintenance of enterocyte quiescence and

nucleotide excision repair by promoting H3K9 acetylation at sites of damage.

(2010b). E2F1 localizes to sites of UV-induced DNA damage to enhance nucleotide

required for induction of the infection-specific form of cellular E2F activity. *Genes* 

Degradation of E2F by the ubiquitin-proteasome pathway: regulation by retinoblastoma family proteins and adenovirus transforming proteins. *Genes Dev* 

DP-1 is required for binding to the adenovirus E4 (ORF6/7) protein. *J Virol* 68,

complex in timely elimination of E2F upon initiation of DNA replication in

and relaxed chromatin structure in Rb-deficient fibroblasts. *Proc Natl Acad Sci U S A* 

(1995). E2F-5, a new E2F family member that interacts with p130 in vivo. *Mol Cell* 

product protects E2F-1 from degradation by the ubiquitin-proteasome pathway.

Trip-Br: a novel family of PHD zing finger- and bromodomain-interacting proteins that regulate the transcriptional activity of E2F-1/DP-1. *EMBO J* 202273-2285).


D'Souza, S.J.A., Vespa, A., Murkherjee, S., Maher, A., Pajak, S., and Dagnino, L. (2002). E2F-1 is essential for normal epidermal wound repair. *J Biol Chem* 27710626-10632). DeCaprio, J.A. (2009). How the Rb tumor suppressor structure and function was revealed by

del Pozo, J.C., Boniotti, M.B., and Gutierrez, C. (2002). Arabidopsis E2Fc functions in cell

Deschenes, C., Alvarez, L., Lizotte, M.E., Vezina, A., and Rivard, N. (2004). The

Dick, F.A. (2007). Structure-function analysis of the retinoblastoma tumor suppressor

Dominguez-Brauer, C., Chen, Y.J., Brauer, P.M., Pimkina, J., and Raychaudhuri, P. (2009).

Dynlacht, B.D., Moberg, K., Lees, J.A., Harlow, E., and Zhu, L. (1997). Specific regulation of E2F family members by cyclin-dependent kinases. *Mol Cell Biol* 17, 7.(3867-3875). Dyson, N and Harlow, E. (1992). Adenovirus E1A targets key regulators of cell proliferation.

Eckner, R., Ludlow, J.W., Lill, N.L., Oldread, E., Arany, Z., Modjtahedi, N., DeCaprio, J.A.,

Fagan, R., Flint, K.J., and Jones, N. (1994). Phosphorylation of E2F-1 modulates its

Farhana, L., Dawson, M., Rishi, A.K., Zhang, Y., Van Buren, E., Trivedi, C., Reichert, U.,

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

Flemington, E.K., Speck, S.H., and Kaelin, W.J. (1993). E2F-1 mediated transactivation is

Galbiati, L., Mendoza-Maldonado, R., Gutierrez, M.I., and Giacca, M. (2005). Regulation of

Garcia-Alvarez, G., Ventura, V., Ros, O., Gil, J., and Tauler, A. (2007). Glycogen synthase

Giangrande, P., Hallstrom, T.C., Tunyaplin, C., Calame, K., and Nevins, J.R. (2003).

division and is degraded by the ubiquitin-SCF(AtSKP2) pathway in response to

nucleocytoplasmic shuttling of E2F4 is involved in the regulation of human intestinal epithelial cell proliferation and differentiation. *J Cell Physiol* 199, 2.(262-

ARF stimulates XPC to trigger nucleotide excision repair by regulating the

Livingston, D.M., and Morgan, J.A. (1996). Association of p300 and CBP with

interaction with the retinoblastoma gene product and the adenoviral E4 19 kDa

Fang, G., Kirschner, M.W., and Fontana, J.A. (2002). Cyclin B and E2F-1 expression in prostate carcinoma cells treated with the novel retinoid CD437 are regulated by

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

inhibited by complex formation with the retinoblastoma susceptibility gene

E2F1 after DNA damage by p300-mediated acetylation and ubiquitination. *Cell* 

kinase-3beta binds to E2F1 and regulates its transcriptional activity. *Biochim Biophys* 

Identification of E-box factor TFE3 as a functional partner for the E2F3 transcription

the study of Adenovirus and SV40. *Virology* 384, 2.(274-284).

protein - is the whole a sum of its parts? *Cell Div* 226).

repressor complex of E2F4. *EMBO Rep* 10, 9.(1036-1042).

simian virus 40 large T antigen. *Mol Cell Biol* 16, 7.(3454-3464).

the ubiquitin-mediated pathway. *Cancer Res* 623842-3849).

suppress proliferation. *Cell* 85, 4.(549-561).

product. *Proc Natl Acad Sci USA*, 90.(

factor. *Mol Cell Biol* 233707-3720).

light. *Plant Cell* 14, 12.(3057-3071).

*Cancer Surveys* 12.(161-195).

protein. *Cell* 78799-811).

*Cycle* 4930-939).

*Acta* 1773375-382).

273).


Post-Transcriptional Regulation of E2F Transcription Factors: Fine-Tuning

proliferation. *Mol Cancer Res* 1, 13.(948-958).

*Res* 68, 7.(2094-2105).

senescence. *Oncogene*.

response. *J Exp Bot*.

*Nucleic Acids Res*.

38.(3360-3370).

865).

2199).

1844).

1158).

signal transduction pathways. *Circ Res* 93, 10.(932-940).

DNA Repair, Cell Cycle Progression and Survival in Development & Disease 179

Kong, H.J., Yu, H.J., Hong, S., Park, M.J., Choi, Y.H., An, W.G., Lee, J.W., and Cheong, J.

Kozaki, K., Imoto, I., Mogi, S., Omura, K., and Inazawa, J. (2008). Exploration of tumor-

Krek, W., Xu, G., and Livingston, D.M. (1995). Cyclin A-kinase regulation of E2F-1 DNA

Lammens, T., Li, J., Leone, G., and De Veylder, L. (2009). Atypical E2Fs: new players in the

Lanigan, F., Geraghty, J.G., and Bracken, A.P. (2011). Transcriptional regulation of cellular

Lario, L.D., Ramirez-Parra, E., Gutierrez, C., Casati, P., and Spampinato, C.P. (2011).

Lee, B.K., Bhinge, A.A., and Iyer, V.R. (2011). Wide-ranging functions of E2F4 in

Lee, J.O., Russo, A.A., and Pavletich, N.P. (1998). Structure of the retinoblastoma tumour-

Lee, K.H., Chen, Y.L., Yeh, S.D., Hsiao, M., Lin, J.T., Goan, Y.G., and Lu, P.J. (2009).

Levitt, N.C., and Hickson, I.D. (2002). Caretaker tumour suppressor genes that defend

Li, W.W., Fan, J., Hochhauser, D., and Bertino, J.R. (1997). Overexpression of p21waf1

Liao, C.C., Tsai, C.Y., Chang, W.C., Lee, W.H., and Wang, J.M. (2010). RB.E2F1 complex

Lin, P.S., McPherson, L.A., Chen, A.Y., Sage, J., and Ford, J.M. (2009). The role of the

Lin, W.-C., Lin, F.-T., and Nevins, J.R. (2001). Selective induction of E2F1 in response to

nucleotide excision repair. *DNA Repair (Amst)* 8, 7.(795-802).

genome integrity. *Trends Mol Med* 8, 4.(179-186).

*Biol Chem* 285, 43.(33134-33143).

E2F transcription factor family. *Trends Cell Biol* 19, 3.(111-118).

requirement of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase

(2003). Interaction and functional cooperation of the cancer-amplified transcriptional coactivator activating signal cointegrator-2 and E2F-1 in cell

suppressive microRNAs silenced by DNA hypermethylation in oral cancer. *Cancer* 

binding function underlies suppression of an S phase checkpoint. *Cell* 83, 7.(1149-

Regulation of plant MSH2 and MSH6 genes in the UV-B-induced DNA damage

transcriptional activation and repression revealed by genome-wide analysis.

suppressor pocket domain bound to a peptide from HPV E7. *Nature* 391, 6670.(859-

MicroRNA-330 acts as tumor suppressor and induces apoptosis of prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation. *Oncogene* 28,

leads to increased inhibition of E2F-1 phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells. *Cancer Res* 57, 11.(2193-

mediates DNA damage responses through transcriptional regulation of ZBRK1. *J* 

retinoblastoma/E2F1 tumor suppressor pathway in the lesion recognition step of

DNA damage, mediated by ATM-dependent phosphorylation. *Genes Dev* 151833-


Huang, Y.C., Misquitta, S., Blond, S.Y., Adams, E., and Colman, R.F. (2008). Catalytically

electrostatic interaction between subunits. *J Biol Chem* 283, 47.(32880-32888). Ianari, A., Gallo, R., Palma, M., Alesse, E., and Gulino, A. (2004). Specific role for

Ingram, L., Munro, S., Coutts, A.S., and La Thangue, N.B. (2011). E2F-1 regulation by an

Ishida, H., Masuhiro, Y., Fukushima, A., Argueta, J.G., Yamaguchi, N., Shiota, S., and

Ishida, S., Huang, E., Zuzan, H., Spang, R., Leone, G., West, M., and Nevins, J.R. (2001). Role

Ivanova, I.A., D'Souza, S.J.A., and Dagnino, L. (2005). Signalling in the epidermis: The E2F

Ivanova, I.A., D'Souza, S.J.A., and Dagnino, L. (2006). E2F stability is regulated by a novel-

Ivanova, I.A., and Dagnino, L. (2007). Activation of p38- and CRM1-dependent nuclear

Ivanova, I.A., Nakrieko, K.A., and Dagnino, L. (2009). Phosphorylation by p38 MAP kinase

Ivanova, I.A., Vespa, A., and Dagnino, L. (2007). A novel mechanism of E2F1 regulation via

Johnson, P.F. (2005). Molecular stop signs: regulation of cell-cycle arrest by C/EBP

Judah, D., Chang, W.Y., and Dagnino, L. (2010). EBP1 is a novel E2F target gene regulated

Kachhap, S.K., Rosmus, N., Collis, S.J., Kortenhorst, M.S., Wissing, M.D., Hedayati, M.,

Kontaki, H., and Talianidis, I. (2010). Lysine methylation regulates E2F1-induced cell death.

Kishore, R., Luedemann, C., Bord, E., Goukassian, D., and Losordo, D.W. (2003). Tumor

transcription factors. *J Cell Sci* 118, Pt 12.(2545-2555).

by transforming growth factor-beta. *PLoS One* 5, 11.(e13941).

response to DNA damage. *J Biol Chem* 27930830-30835).

DNA microarrays. *Mol Cell Biol* 214684-4699).

transformation. *Int J Biol Sci* 187-95).

*Oncogene* 25430-437).

261147-1154).

62186-2195).

*PLoS One* 5, 6.(e11208).

*Molec Cell* 39, 2. (152-160)

63).

132).

24648).

active monomer of glutathione S-transferase pi and key residues involved in the

p300/CREB-binding protein-associated factor activity in E2F1 stabilization in

unusual DNA damage-responsive DP partner subunit. *Cell Death Differ* 18, 1.(122-

Hanazawa, S. (2005). Identification and characterization of novel isoforms of human DP-1: DP-1{alpha} regulates the transcriptional activity of E2F1 as well as cell cycle progression in a dominant-negative manner. *J Biol Chem* 280, 26.(24642-

for E2F in control of both DNA replication and mitotic functions as revealed from

cell cycle regulatory pathway in epidermal morphogenesis, regeneration and

PKC/p38 MAP kinase signalling pathway during keratinocyte differentiation.

export promotes E2F1 degradation during keratinocyte differentiation. *Oncogene* 

is required for E2F1 degradation and keratinocyte differentiation. *Oncogene* 2852-

nucleocytoplasmic shuttling: determinants of nuclear import and export. *Cell Cycle* 

Shabbeer, S., Mendonca, J., Deangelis, J., Marchionni, L.*, et al.* (2010). Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor.

necrosis factor-mediated E2F1 suppression in endothelial cells: differential

requirement of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase signal transduction pathways. *Circ Res* 93, 10.(932-940).


Post-Transcriptional Regulation of E2F Transcription Factors: Fine-Tuning

on versatility. *Cell Mol Life Sci* 66, 6.(994-1009).

prometaphase. *Cell Cycle* 9, 19.(3956-3964).

3.(856-865).

8.(1437-1446).

558).

145).

*Cell* 13, 3.(272-286).

18, 11.(528-535).

7.(1200-1211).

*Genome Res* 18, 11.(1763-1777).

*Cell Biol* 24, 24.(10986-10994).

DNA Repair, Cell Cycle Progression and Survival in Development & Disease 181

Morrison, A.J., Sardet, C., and Herrera, R.E. (2002). Retinoblastoma protein transcriptional

Nemethova, M., Smutny, M., and Wintersberger, E. (2004). Transactivation of E2F-regulated

Nouspikel, T. (2009). DNA repair in mammalian cells : Nucleotide excision repair: variations

O'Donnell, K.A., Wentzel, E.A., Zeller, K.I., Dang, C.V., and Mendell, J.T. (2005). c-Mycregulated microRNAs modulate E2F1 expression. *Nature* 435, 7043.(839-843). Ohta, T., and Xiong, Y. (2001). Phosphorylation- and SKP1-independent in vitro ubiquitination of E2F1 by multiple ROC-Cullin ligases. *Cancer Res* 611347-1353). Ormondroyd, E., de la Luna, S., and La Thangue, N.B. (1995). A new member of the DP

Ozaki, T., Okoshi, R., Sang, M., Kubo, N., and Nakagawara, A. (2009). Acetylation status of

Pediconi, N., Ianari, A., Costanzo, A., Belloni, L., Gallo, R., Cimino, L., Porcellini,

Petrocca, F., Visone, R., Onelli, M.R., Shah, M.H., Nicoloso, M.S., de Martino, I., Iliopoulos,

Pickering, M.T., Stadler, B.M., and Kowalik, T.F. (2009). miR-17 and miR-20a temper an

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

Prost, S., Lu, P., Caldwell, H., and Harrison, D. (2007). E2F regulates DDB2: consequences

Rabinovich, A., Jin, V.X., Rabinovich, R., Xu, X., and Farnham, P.J. (2008). E2F in vivo

Raychaudhuri, P., Bagchi, S., Devoto, S.H., Knaus, V. B., Moran, E. and Nevins, J. R. (1991).

for DNA repair in Rb-deficient cells. *Oncogene* 26, 24.(3572-3581).

tumor suppressor p73. *Biochem Biophys Res Commun* 386, 1.(207-211). Peart, M.J., Poyurovsky, M.V., Kass, E.M., Urist, M., Verschuren, E.W., Summers, M.K.,

Nevins, J.R. (2001). The Rb/E2F pathway and cancer. *Human Mole Genet* 10699-703).

repression through histone deacetylation of a single nucleosome. *Mol Cell Biol* 22,

genes by polyomavirus large T antigen: evidence for a two-step mechanism. *Mol* 

family, DP-3, with distinct protein products suggests a regulatory role for alternative splicing in the cell cycle transcription factor DRTF1/E2F. *Oncogene* 11,

E2F-1 has an important role in the regulation of E2F-1-mediated transactivation of

Jackson, P.K., and Prives, C. (2010). APC/C(Cdc20) targets E2F1 for degradation in

A., Screpanti, I., Balsano, C., Alesse, E.*, et al.* (2003). Differential regulation of E2F1 apoptotic target genes in response to DNA damage. *Nat Cell Biol* 5552-

D., Pilozzi, E., Liu, C.G., Negrini, M.*, et al.* (2008). E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. *Cancer* 

E2F1-induced G1 checkpoint to regulate cell cycle progression. *Oncogene* 28, 1.(140-

binding specificity: comparison of consensus versus nonconsensus binding sites.

Domains of the adenovirus E1A protein required for oncogenenic activity are also required for dissociation of E2F transcription factor complexes. *Genes Dev* 5,


Liu, X. and R. Marmorstein (2007). Structure of the retinoblastoma protein bound to

Lopez, R.G., Garcia-Silva, S., Moore, S.J., Bereshchenko, O., Martinez-Cruz, A.B., Ermakova,

Ludlow, J.W., DeCaprio, J.A., Huang, C.M., Lee, W.H., Paucha, E., and Livingston, D.M.

Mann, D.J., and Jones, N.C. (1996). E2F-1 but not E2F-4 can overcome p16-induced G1 cell-

Marabese, M., Vikhanskaya, F., Rainelli, C., Sakai, T., and Broggini, M. (2003). DNA damage

Marti, A., Wirbelauer, C., Scheffner, M., and Krek, W. (1999). Interaction between ubiquitin-

Martinez-Balbas, M.A., Bauer, U.M., Nielsen, S.J., Brehm, A., and Kouzarides, T. (2000).

Marzio, G., Wagener, C., Gutierrez, M.I., Cartwright, P., Helin, K., and Giacca, M. (2000).

Masuhiro, Y., Kayama, K., Fukushima, A., Baba, K., Soutsu, M., Kamiya, Y., Gotoh, M.,

McClellan, K.A., and Slack, R.S. (2007). Specific in vivo roles for E2Fs in differentiation and

Meng, R.D., Phillips, P., and El-Deiry, W.S. (1999). p53-independent increase in E2F-1

Milton, A., Luoto, K., Ingram, L., Munro, S., Logan, N., Graham, A.L., Brummelkamp, T.R.,

Moody, C.A., and Laimins, L.A. (2010). Human papillomavirus oncoproteins: pathways to

Morris, L., Allen, K.E., and La Thangue, N.B. (2000). Regulation of E2F transcription by

member of the DP family of E2F subunits. *Oncogene* 25, 22.(3212-3218). Moberg, K., Starz, M.A., and Lees, J.A. (1996). E2F-4 switches from p130 to p107 and pRB in

response to cell cycle reentry. *Mol Cell Biol* 161436-1449).

transformation. *Nat Rev Cancer* 10, 8.(550-560).

Regulation of E2F1 activity by acetylation. *Embo J* 19, 4.(662-671).

tumor suppressor. *Genes Dev* 21,21. (2711-2716).

differentiation. *Nat Cell Biol* 11, 10.(1181-1190).

cycle arrest. *Curr Biol* 6, 4.(474-483).

*Nature Cell Biol* 114-19).

*Chem* 275, 15.(10887-10892).

46.(31575-31583).

*Oncol* 14, 1.(5-14).

4.(232-239).

E2F1. *Nucleic Acids Res* 31, 22.(6624-6632).

development. *Cell Cycle* 6, 23.(2917-2927).

(57-65).

adenovirus E1A reveals the molecular basis for viral oncoprotein inactivation of a

O., Kurz, E., Paramio, J.M., and Nerlov, C. (2009). C/EBPalpha and beta couple interfollicular keratinocyte proliferation arrest to commitment and terminal

(1989). SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family. *Cell* 56, 1.

induces transcriptional activation of p73 by removing C-EBPalpha repression on

protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation.

E2F family members are differentially regulated by reversible acetylation. *J Biol* 

Yamaguchi, N., and Hanazawa, S. (2008). SOCS-3 inhibits E2F/DP-1 transcriptional activity and cell cycle progression via interaction with DP-1. *J Biol Chem* 283,

expression enhances the cytotoxic effects of etoposide and of adriamycin. *Int J* 

Hijmans, E.M., Bernards, R., and La Thangue, N.B. (2006). A functionally distinct

cyclin E-Cdk2 kinase mediated through p300/CBP co-activators. *Nat Cell Biol* 2,


Post-Transcriptional Regulation of E2F Transcription Factors: Fine-Tuning

in old mice. *J Biol Chem* 283, 38.(26169-26178).

*Nature* 375812-815).

*Chem* 27828516-28522).

2134).

DNA Repair, Cell Cycle Progression and Survival in Development & Disease 183

Wang, B., Liu, K., Lin, F.T., and Lin, W.C. (2004). A role for 14-3-3 tau in E2F1 stabilization and DNA damage-induced apoptosis. *J Biol Chem* 279, 52.(54140-54152). Wang, G.L., Salisbury, E., Shi, X., Timchenko, L., Medrano, E.E., and Timchenko, N.A.

Wang, H., Larris, B., Peiris, T.H., Zhang, L., Le Lay, J., Gao, Y., and Greenbaum, L.E. (2007).

Wan, Z., Zhi, N., Wong, S., Keyvanfar, K., Liu, D., Raghvachari, N., Munson, P. J., Su, S.

Weber, J.D., Taylor, L.J., Roussel, M.F., Sherr, C.J., and Bar-Sagi, D. (1999). Nucleolar Arf

Weintraub, S.J., Chow, K.N., Luo, R.X., Zhang, S.H., He, D., and Dean, D.C. (1995).

Wikonkal, N.M., Remenyik, E., Knezevic, D., Zhang, W., Liu, M., Zhao, H., Berton, T.R., and

Wong, C.F., Barnes, L.M., Dahler, A.L., Smith, L., Serewko-Auret, M.M., Popa, C., Abdul-

Woods, K., Thomson, J.M., and Hammond, S.M. (2007). Direct regulation of an

Xiao, B., Spencer, J., Clements, A., Ali-Khan, N., Mittnacht, S., Broceno, C., Burghammer, M.,

Xie, Q., Bai, Y., Wu, J., Sun, Y., Wang, Y., Zhang, Y., Mei. P., and Yuan, Z. (2011)

Xu, T., Zhu, Y., Xiong, Y., Ge, Y.Y., Yun, J.P., and Zhuang, S.M. (2009). MicroRNA-195

Yang, J., Song, K., Krebs, T. L., Jackson, M. W., and Danielpour, D. (2008). Rb/E2F4 and

Zaragoza, K., Begay, V., Schuetz, A., Heinemann, U., and Leutz, A. (2010). Repression of

Zhang, X., Wan, G., Berger, F.G., He, X., and Lu, X. (2011). The ATM Kinase Induces MicroRNA Biogenesis in the DNA Damage Response. *Mol Cell* 41, 4.(371-383).

CREB-binding protein/P300. *J Biol Chem* 282, 34.(24679-24688).

of transcription factors. *J Clin Invest* 120, 10.(3530-3544).

sequesters Mdm2 and activates p53. *Nat Cell Biol* 1, 1.(20-26).

sensitivity in Trp53-deficient mice. *Nat Cell Biol* 5655-660).

its regulation. *Proc Natl Acad Sci U S A* 100, 5.(2363-2368).

*Recept Signal Transduct Res* 31, 2. (139-146).

carcinoma cells. *Hepatology* 50, 1.(113-121).

*Oncogene* 27, 40.(5226-5238).

*Cell Biol* 30, 9.(2293-2304).

(2008). HDAC1 cooperates with C/EBPalpha in the inhibition of liver proliferation

C/EBPbeta activates E2F-regulated genes in vivo via recruitment of the coactivator

Malide, D., Kajigaya, S., and Young, N. S.(2010). Human parvovirus B19 cauyses cell cycle arrest of human erythroid progenitors via deregulation of the E2F family

Mechanism of active transcriptional repression by the retinoblastoma protein.

Johnson, D.G. (2003). Inactivating E2f1 reverts apoptosis resistance and cancer

Jabbar, I., and Saunders, N.A. (2003). E2F modulates keratinocyte squamous differentiation: Implications for E2F inhibition in squamous cell carcinoma. *J Biol* 

oncogenic micro-RNA cluster by E2F transcription factors. *J Biol Chem* 282, 4.(2130-

Perrakis, A., Marmorstein, R., and Gamblin, S.J. (2003). Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of

Methylation-mediated regulation of E2F1 in DANN damage-induced cell death. *J* 

suppresses tumorigenicity and regulates G1/S transition of human hepatocellular

Smad2/3 link survivin to TGF-beta-induced apoptosis and tumor progression.

transcriptional activity of C/EBPalpha by E2F-dimerization partner complexes. *Mol* 


Ramathal, C., Bagchi, I.C., and Bagchi, M.K. (2010). Lack of CCAAT enhancer binding

Real, S., Espada, L., Espinet, C., Santidrian, A.F., and Tauler, A. (2010). Study of the in vivo phosphorylation of E2F1 on Ser403. *Biochim Biophys Acta* 1803, 8.(912-918). Schlisio, S., Halperin, T., Vidal, M., and Nevins, J.R. (2002). Interaction of YY1 with E2Fs,

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

Shin, E.K., Shin, A., Paulding, C., Schaffhausen, B., and Yee, A.S. (1995). Multiple change in

Siafakas, R., and Richardson, D.R. (2009). Growth arrest and DNA damage-45 alpha

Sim, K.G., Zang, Z., Yang, C.M., Bonventre, J.V., and Hsu, S.I. (2004). TRIP-Br links E2F to

Smith, E.J., Leone, G., DeGregori, J., Jakoi, L., and Nevins, J.R. (1996). The accumulation of

Sullivan, C.S., Cantalupo, P., and Pipas, J.M. (2000). The molecular chaperone activity of

Sylvestre, Y., De Guire, V., Querido, E., Mukhopadhyay, U.K., Bourdeau, V., Major, F.,

Tazawa, H., Tsuchiya, N., Izumiya, M., and Nakagama, H. (2007). Tumor-suppressive

Timchenko, N.A., Wilde, M., Iakova, P., Albrecht, J.H., and Darlington, G.J. (1999).

Truscott, M., Harada, R., Vadnais, C., Robert, F., and Nepveu, A. (2008). p110 CUX1

van Ginkel, P.R., Hsiao, K.M., Schjerven, H., and Farnham, P.J. (1997). E2F-mediated growth

Vandel, L., and Kouzarides, T. (1999). Residues phosphorylated by TFIIH are required fpr

an ATP-dependent mechanism. *Mol Cell Biol* 20, 17.(6233-6243).

(GADD45alpha). *Int J Biochem Cell Biol* 41986-989).

state. *Mol Cell Biol* 16, 12.(6965-6976).

loop. *J Biol Chem* 282, 4.(2135-2143).

adipocytes. *Nucleic Acids Res* 27, 17.(3621-3630).

cycle-regulated genes. *Mol Cell Biol* 28, 10.(3127-3138).

E2F-1 degradation during S-phase. *EMBO J* 184280-4291).

*Mol Cell Biol* 30, 7.(1607-1619).

21, 21.(5775-5786).

4.(2252-2262).

1304).

15477).

18374).

*Cancer* 3, 3.(155-168).

protein beta (C/EBPbeta) in uterine epithelial cells impairs estrogen-induced DNA replication, induces DNA damage response pathways, and promotes apoptosis.

mediated by RYBP, provides a mechanism for specificity of E2F function. *EMBO J* 

E2F function and regulation occur upon muscle differentiation. *Mol Cell Biol* 15,

novel functions in the regulation of cyclin E expression during cell cycle progression and in the maintenance of genomic stability. *Cell Cycle* 3, 10.(1296-

an E2F-p130 transcriptional repressor distinguishes a G0 cell state from a G1 cell

simian virus 40 large T antigen is required to disrupt Rb-E2F family complexes by

Ferbeyre, G., and Chartrand, P. (2007). An E2F/miR-20a autoregulatory feedback

miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. *Proc Natl Acad Sci U S A* 104, 39.(15472-

E2F/p107 and E2F/p130 complexes are regulated by C/EBPalpha in 3T3-L1

cooperates with E2F transcription factors in the transcriptional activation of cell

regulation requires transcription factor cooperation. *J Biol Chem* 272, 29.(18367-


**1. Introduction** 

**11** 

*Poland* 

Dorota Rybaczek

 *(Szymborska, 1993)* 

**Eidetic Analysis of the Premature** 

*'Why does this written doe bound through these written woods?* 

An exact transfer of genetic information depends on the accuracy of mechanisms duplicating DNA molecules in the S-phase and the precise division sister chromosomes during mitosis. The regulation systems of these processes (checkpoints) not only control the activation course of the factors imposing different metabolic specificity on each of the cell cycle phases, but first of all – supervising the proper chronology of events – they condition the behavior of the structural and functional genome integrity. Checkpoints receive signals of all abnormalities or structural damages to DNA and in response evoke reactions inhibiting successive transitions through the cell cycle to enable the expression of specific genes and activation of DNA repair factors. One of the easily perceptible effects of disorders in this signaling system is the induction of premature chromosome condensation (PCC). The present chapter is a review of the ways and mode of the induction of PCC. The term 'PCC' is inseparably associated with Johnson & Rao (1970) and their experiments on the premature mitosis induced by fusion of interphase and mitotic HeLa cells (G1/M, S/M and G2/M) which were originally carried out using Sendai virus. PCC process can be also induced by chemical signals. Drug-induced PCC provides the new knowledge that DNA replication is tightly coupled with the premature chromosome condensation and that the genome stability results first of all from the alternation of the S-phase and mitosis. The main objective of this review is to show that the PCC induction is possible from various subperiods of cell cycle. Moreover, it has been shown that there are cause-and-effect relationships between the chromosome structure defining 'PCC phenotype' and subperiods, e.g. of the S-phase, initiating the biosynthesis of 'early' or 'late' replicons. Attempts have been made to find answers to questions such as: How to force cells to break out of the rules being developed by Nature for billions of years? How – despite the interrupted, still unterminated process of genome replication – to force a cell to initiate its division? What mechanisms annihilate the subordination principle verified in the course of evolution: first create (DNA-duplicating Sphase) and then divide (mitosis – a stage of DNA condensation and formation of sister

*Department of Cytophysiology, University of Łódź*

*(…) Perched on four slim legs borrowed from the truth, She pricks up her ears beneath my fingertips (…)'* 

**Chromosome Condensation Process** 

Zhu, J.W., DeRyckere, D., Li, F.X., Wan, Y.Y., and DeGregori, J. (1999). A role for E2F1 in the induction of ARF, p53, and apoptosis during thymic negative selection. *Cell Growth Differ* 10, 12.(829-838).
