DNA Repair Mechanisms and Initiation in Carcinogenesis: An Update

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