**3.5 DNA repair for psoralen-DNA adducts**

DNA alkylation by psoralen can lead to inter-strand crosslinks (ICL) or mono-adducts (MA). Psoralen-ICLs (Figure 9) are eliminated during the replication process, associated with HR (**1**), MMR (**2**) and error-prone translesion DNA polymerases (Dronkert & Kanaar, 2001). NER proteins such as XPC/hHR23B complex and XPA/RPA complexes are also implicated in the repair of psoralen-ICL (Thoma et al., 2005) and could cooperate with MMR to excise the lesions (Zhao et al., 2009). By contrast, thymine-psoralen mono-adducts (**3**) are moderately excised from the DNA by the NER system (Vasquez et al., 2002), because of adduct recognition by HMG-B1 which recruits RPA helicase (**4**) (Lange et al., 2009) or by MMR

Fig. 9. DNA repair pathways for psoralen-induced DNA damage.

(Q. Wu et al., 2005; 2008). Psoralen monoadducts are good substrates for 3-Methyladenine DNA glycosylase (MPG) (Maor-Shoshani et al., 2008) and the human oxidative DNA glycosylase, NEIL1, which catalyses the ,-elimination at AP site, leaving a 3'-P termini at the resulting SSB (**5**) (Couvé-Privat et al., 2007). Fanconi anemia pathway was also implicated in the repair process, in link with NEIL1 stability and NER efficiency (Macé-Aimé et al., 2010).

### **3.6 DNA repair for benzoacronycine-DNA adducts**

S23906-1 alkylates the DNA in the minor groove and induces a strong destabilization of the DNA helix. Two reactive acetate groups are positioned on asymmetric carbons leading to four pure enantiomers: 2 *cis* (1R;2R and 1S;2S) (the *cis*-racemate being S23906-1) and two *trans* (1R;2S and 1S;2R) isomers. Both pure enantiomers react with DNA and destabilize the DNA helix but at different extends. The most potent DNA destabilizing ones (1S;2S and 1S;2R) being those presenting the most active anti-tumour activities in animal models (Depauw et al., 2009). Therefore, the rate of DNA destabilization is different depending on the orientation of the core of the adducts regarding the opened drug/DNA structure, and correlates with different cellular and anti-tumour effects. Such strong destabilisation could affect single-stranded endonuclease and DNA repair activities. There is currently only partial knowledge on the repair of S23906-1 DNA adducts. The NER proteins XPC and CSB are involved in cell sensitivity to S23906-1, associated with both global genome repair and transcription-coupled NER (Rocca et al., 2010). ATR coordination, RPA recognition and Chk1 activation were also implicated in responses to S23906-1 DNA damages (Soares et al., 2011). Process of the lesions is associated with DSB as secondary DNA lesions important for cytotoxicity of S23906-1, associated with histone H2AX phosphorylation (Léonce et al., 2006). Of major interest, the most potent destabilizing isomer of S23906-1 was evidenced to be also the most cytotoxic on cellular models and the most efficient on xenografted animal models (Depauw et al., 2009). Current ongoing research is identifying proteins implicated in S23906-1/DNA adduct recognition and evaluating their impact on S23906-1 cytotoxic activity (personal communication). Locally destabilized DNA could favour the recognition of DNA lesion by "DNA repair sensors" thus increasing the efficiency/kinetic of the removal of the DNA lesion.
