Structure and reactivity of complex DNA lesions: clustered abasic sites as a case study
Résumé
Although investigations on DNA damage and repair started several decades ago, the complexity and vastness of their chemical aspects are still matter of research as their molecular mechanisms remain ill-defined. The structural signature of DNA lesions is crucial for their repair, but only few structural data are available from X-Ray and NMR studies. In order to gain insights into their formation and structure, we investigated of a series of complex lesions within the double helix. Abasic sites (Ap) are one of the systems we tackled. These lesions result from the cleavage of the nucleotide glycosidic bond, leaving only the deoxyribose moiety in the DNA strand. They can be generated by exposure to ionizing radiation or as the products of enzymes involved in DNA damage response. Ap can be highly genotoxic (mismatch during DNA replication) and cytotoxic (formation of interstrand crosslinks), hence their high biological relevance. We investigated the structural behavior of short oligonucleotides harboring clustered Ap, in order to rationalize experimental repair rate measurements [1]. We also studied their interaction with the human Ap endonuclease, APE1, responsible for their removal. Our approach, based on the use of classical MD simulations, provided insights into the structural signature of clustered Ap withinDNA [2] and their processing by repair enzymes [3]. Our results allowed to improve the understanding of why clustered lesions are so challenging for DNA repair [1]. In line with those studies, we then started to work on the structural behavior of Ap within nucleosomal DNA, which constitute a more realistic yet computationally expensive model (manuscript in preparation). Overall, this PhD thesis work shed new lights on damaged DNA reactivity, structure and repair, which provides perspectives for cell mechanisms understanding and biomedicine. E.B. is grateful to the French Minister of Higher Education and Research for PhD fellowship, and to the COST Action CM1201 and Labex PRIMES for fundings. The PSMN is acknowledged for computational resources.
1 Georgalikas, A. G.; Bennett, P. V.; Sutherland, B. M. NAR 2002.
2 Bignon, E.; Gattuso, H.; Morell, C.; Dehez, F.; Georgakilas, A. G.; Monari, A.; Dumont, E. NAR 2016.
3 Gattuso, H.; Durand, E.; Bignon, E.; Morell, C.; Georgakilas, A. G.; Dumont, E.; Chipot, C.; Dehez, F.; Monari, A. JPCL 2016.