**Part 4**

**Insights into Therapeutic Strategies** 

414 Selected Topics in DNA Repair

Yang, C. G., Yi, C. Q., Duguid, E. M., Sullivan, C. T., Jian, X., Rice, P. A., & He, C. (2008).

Yang, X., Wang, X. B., Vorpagel, E. R., & Wang, L. S. (2004). "Direct experimental

Yao, L. S., Li, Y., Wu, Y., Liu, A. Z., & Yan, H. G. (2005). "Product release is rate-limiting in

Yu, B., Edstrom, W. C., Benach, J., Hamuro, Y., Weber, P. C., Gibney, B. R., & Hunt, J. F.

dsDNA." *Nature*, 452(7190), 961-U4.

*Biochemistry*, 44(15), 5940-5947.

enzyme AlkB." *Nature*, 439(7078), 879-884.

17592.

"Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to

observation of the low ionization potentials of guanine in free oligonucleotides by using photoelectron spectroscopy." *Proc. Natl. Acad. Sci. U. S. A.*, 101(51), 17588-

the activation of the prodrug 5-fluorocytosine by yeast cytosine deaminase."

(2006). "Crystal structures of catalytic complexes of the oxidative DNA/RNA repair

**18** 

*1Canada 2Bulgaria* 

OH) are the

OH (G-values of

**DNA Radiosensitization: The Search for Repair** 

More than half of all cancer patients receive radiotherapy (RT) as part of their treatment regimens. The cytotoxicity of ionizing radiation is mainly mediated by the ensuing DNA damage. Double-stranded DNA breaks (DSB) are generally accepted to be the most important lesions for the induction of cell death by ionizing radiation because they are much more difficult to repair than single strand breaks, although their radiation yield is very low, at two orders of magnitude less than that of single strand breaks (SSB) (Hempel & Mildenberger, 1987). The role of other DNA lesions such as base damage and interstrand crosslinks in cell killing has not been yet fully elucidated. Gamma-radiation inflicts DNA damage *via* two separated processes: i) direct interaction with DNA and; ii) indirect damage

species primarily responsible for strand break formation and DNA base damage (> 35%).

~ 2.8x10-7 mol.J-1), participate in only ~ 8% of the total damage and the exact nature of DNA damage formed *in vivo* by e¯aq is obscure (Nabben *et al*., 1982). In vertebrate cells, the majority of RT-induced DSB are repaired by non-homologous end joining (NHEJ) with some contribution from homologous recombination repair (HRR) during the late S and G2 phases of the cell cycle (Jackson, 2002; Takata *et al.*, 1998). The repair of other DNA damages, such as interstrand crosslinks (ICL) is more complicated and less understood (Wang, 2007; Moldovan & D'Andrea, 2009). ICLs can be recognized by the nucleotide excision repair (NER) system and it is accepted that ICL repair involves nucleolytic cleavage at or near the site of ICL to produce a suitable substrate that can subsequently be repaired by homologous recombination (HR) (D'Andrea & Grompe, 2003; Moldovan & D'Andrea, 2009a, Liu *et al.*,

An approach to improve the effectiveness of RT is either to enhance the formation of lethal DNA lesions, or to use inhibitors of DNA repair pathways (or both) and thus to render tumor

OH,

(Michaels & Hunt, 1978). Among the H2O derived radicals, hydroxyl radicals (

Hydrated electrons, e¯aq, which are generated at a yield comparable to the

**1. Introduction** 

2010).

produced by secondary radicals (

**Refractive Lesions Including Double Strand** 

Tsvetan G. Gantchev1,2, Marie-Eve Dextraze1 and Darel J. Hunting1

*1Department of Nuclear Medicine & Radiobiology, Faculté de medicine,* 

**Breaks and Interstrand Crosslinks** 

*2Department of Gene Regulations, Institute of Molecular Biology,* 

*Université de Sherbrooke, Sherbrooke, Québec,* 

H and e¯aq) generated after water radiolysis

*Bulgarian Academy of Sciences, Sofia,* 
