7.04 - DNA Repair Mechanisms and Initiation in Carcinogenesis: An Update

Abstract

Present models of carcinogenesis imply that apart from the tissue microenvironment the initiation of cancers involves the induction of lesions in DNA, error-prone or lack of DNA repair, the induction of mutations and genomic instability. The present review summarizes recent knowledge on the induction and repair of DNA damage, DNA damage response (DDR) signaling, the main repair pathways and their role in the maintenance of genomic stability and, in case of failure, the relationship to cancer development. Because of the multiplicity and variation of damage inflicted on human cells from endogenous and exogenous sources (normal cell metabolism and mutagenic chemical and physical agents), cells have developed an effective strategy to cope with such internal and external stresses: (1) rapid signaling of the damage, (2) activation of prominent effector proteins by phosphokinases such as ATM, ATR, and DNA-PKcs, (3) induction of cell cycle arrest leaving time for the mobilization of lesion and metabolic state-adapted DNA repair pathway(s). DDR and DNA repair are highly dependent on genetic and epigenetic control mechanisms including modifications in chromatin structure. Complex lesions such as DNA double-strand breaks (DSBs) arising from stalled replication forks, repair intermediates or directly induced chemical or radiation-induced damage are the most refractory to accurate repair. Single-strand breaks, base modifications, and some adducts are more easily repaired than complex lesions such as DNA DSBs or interstrand crosslinks. Inaccurate repair leads to mutations, chromosomal and genomic instability and is cancer prone. The repair pathways (mismatch repair, Base excision repair, nucleotide excision repair, homologous recombination) are very accurate, however, nonhomologous endjoining (NHEJ) and its variant, alternative NHEJ (Alt-NHEJ) are inaccurate. The latter shows that cells tend to use components from other repair systems when certain lesions cannot be completely repaired by one of the main pathways because functional repair proteins are absent (e.g., proteins such as KU, DNA-PKcs, and LigIV are missing). In that case, although acting sequentially in a concerted manner, the fidelity of DNA repair decreases, whereas genomic instability and susceptibility to cancer increases. Detailed analyses of the different repair systems show that they are very closely embedded in normal cellular metabolic networks. Future systems biology analysis of these networks should allow further insights into the relationship between failures in DNA repair and carcinogenic outcomes to the benefit of a better understanding of the mechanisms involved, predictions of carcinogenic risks and the development of new anticancer treatment modalities.