Hypermutability Associated with Double-Strand Break Repair

摘要

Double-strand breaks (DSBs) are the most toxic kind of DNA damage caused by ionizing radiation as well as by a number of other environmental factors and drugs. DSBs lead to gross chromosome rearrangements, genetic disease, and cancer or cell death. However cells can be programmed to generate DSBs in their own DNA. Programmed DSBs are a key element of many biological functions such as meiotic recombination and segregation, adaptive immunity, regulation switches and viral life cycles. Either damage-induced or programmed DSBs should be repaired in order to retain cell viability. Over the last years it has been established that DSB repair can be associated with up to 10,000-fold increase in frequency of base substitutions and small insertions/deletions (indels). This localized hypermutability represents additional genotoxic threat as well as a potential for generating rare multiple mutant alleles with high fitness without overloading the rest of the genome with mutations.