**6. Conclusion**

430 Selected Topics in DNA Repair

**T17**

**O4'**

**T5** 

**T6 (BrdU6)** 

**O4'**

**O4' O4'**

**T7** 

**A16**

Fig. 8. Nearest-neighbour sequence effects in wobble semi-complementary DNA (scDNA) as observed by MD (adapted from Gantchev *et al*. 2005). Schematic presentation of the frequent cross-strand (cs) inter-base contacts formed in the studied 11-mer DNA duplexes containing a single mismatch: T^T or T^BrU, incorporated in the central triplets: d(CTA)(TTG) (A), d(TTT)(ATA) (B) and d(TBrdUT)(ATA) (C): bold dashed lines (most frequently observed cs H-bons), dotted lines (less frequent cs H-bonds). Note that cs contacts in (C) coincide with

chromatin response to DNA damage involves activation of ATP-dependent chromatinremodeling complexes and histone post-translational modification pathways (Peterson & Côte, 2004; Nag & Smerdon, 2009; Méndez-Acuña *et al*., 2010). Again, DSBs recognition and repair in the context of chromatin rearrangement is better studied and understood at the expense of other DNA damages, such as ICLs. One crucial chromatin modification, the phosphorylation of the histone variant H2AX (γH2AX) is perhaps the best example of a histone modification in response to DSB induction in DNA (Van Attikum & Gasser, 2005). Despite the progress achieved in understanding of the repair of certain UV-induced DNA damages (intra-strand crosslinks), *e.g.* cyclobutane pyrimidine dimers (CPD) and 6-4 pyrimidine photoadducts (6-4 PP), or the acetylaminofluorene-guanine (AAF-G) covalent adduct, little is known about the effects of other bulky DNA lesions (*e.g.* ICLs) on the nucleosome structural dynamics and its interplay with the versatile NER pathway (Smerdon & Lieberman, 1978; Pehrson, 1995; Gaillard et al., 2003; Gospodinov & Herceg, 2011). There is a consensus that NER functionality depends primarily on the damage recognition step, which in turn depends on the degree of DNA helix distortion induced by a particular lesion (Cai *et al*., 2007). It has been hypothesized that structurally different interstrand crosslinks would affect chromatin remodeling and damage recognition in different ways, and some ICLs might retain their refractive character to recognition/repair, or at least will exert an altered repair efficacy. Thus, a recent *in vivo* study (Hlavin *et al.*, 2010) confirmed that the structure of synthetic interstrand crosslinks between mismatched bases affects the repair rate (in this case, transcription coupled NER). It can be further hypothesized that PNA-patches hybridized to DNA (*e.g.*, > 8-10 b.p.; PNA- invaded DNA strands, PNA-DNA triple helices, and/or DNA-PNA covalent adducts) would be

those observed also in the presence of e¯aq (Gantchev & Hunting, 2009). These data underline the importance of the wobble DNA dynamic structure for both, interstrand ET and high-frequency opposite-strand atom encounter for the generation of (asymmetric) ICL

**A B and C**

**C5**

**O4' O4'**

**T6**

**O4'**

**A7** 

**G18** 

**T17** 

**O4'** 

**T16** 

(Fig. 1).

In conclusion, there is a need to better understand the parameters which control the formation and repair of complex DNA lesions, such as interstrand crosslinks. Such complex, repair refractive lesions may offer a means to selectively kill tumor cells by taking advantage of either enhanced formation or reduced repair within the tumor environment.
