Breaking bad: The mutagenic effect of DNA repair

摘要: Species survival depends on the faithful replication of genetic information, which is continually monitored and maintained by DNA repair pathways that correct errors thousands lesions arise daily from inherent chemical lability effects genotoxic agents. Nonetheless, neutrally evolving (not under purifying selection) accumulates base substitutions with time (the neutral mutation rate). Thus, processes are not 100% efficient. The rate varies both between within chromosomes. For example it 10-50 fold higher at CpGs than non-CpG positions. Interestingly, sites positively correlated CpG content. Although basis this correlation was immediately apparent, some bioinformatic results were consistent induction mutations flanking sites. Recent studies a model system showed in vivo preformed (mismatches, abasic sites, single stranded nicks) can fact induce DNA. Mismatch (MMR) an essential component for repair-induced mutations, occur as distant 5 kb introduced lesions. Most, but all, involved C TpCpN (G NpGpA) target sequence C-preferring single-stranded specific APOBEC deaminases. APOBEC-mediated limited to our system: others tumors harbor same signature, intermediates RNA-guided endonuclease-mediated genome editing. deaminases participate normal physiological functions such generating inactivate viruses or endogenous retrotransposons, enhance immunoglobulin diversity B cells. recruitment normally error-prone during would have important implications disease, aging evolution. This perspective briefly reviews biochemical literature relevant mutagenesis discusses future directions required understand mechanistic process.