Abstract
In bacteria repair of DNA, double-stranded breaks (DSBs) can occur by mechanisms with varying degrees of mutagenicity. Repair by homologous recombination (HR) with a sister chromosome can be relatively nonmutagenic. Nonhomologous end joining can create small mutations and large genome rearrangements, as can some break-induced DNA replication mechanisms that occur when a DSB-end primes replication using a template with limited sequence identity, as in microhomology-mediated break-induced replication (MMBIR). From bacteria to human cancer cells, stress responses upregulate mechanisms of mutagenesis, including at least three mechanisms in which high-fidelity DSB repair by HR is switched to mutagenic mechanisms via stress responses. In Escherichia coli, stress responses cause a switch from high-fidelity HR-mediated DSB repair to two different mutagenic mechanisms: a point mutagenesis mechanism in which HR repair uses specialized error-prone DNA polymerases instead of the main replicative DNA polymerase, and a genome-rearrangement pathway of apparent MMBIR, which creates copy-number variations (gene amplifications and deletions) and other rearrangements, both activated by the general or starvation stress response. In humans, the hypoxic stress response downregulates proteins of DSB repair via HR, leaving genome-destabilizing nonhomologous and microhomologous repair options. Stress-responsive mutagenic break repair (MBR) creates genetic diversity specifically when cells are poorly adapted to their environment (i.e., when stressed), potentially accelerating adaptation. MBR also localizes mutations to regions near DSBs, which may allow concerted evolution of functions of genes and linked gene groups - a major problem in evolution of protein/protein-machine function. Temporal regulation of mutagenesis by stress responses and spatial localization near DSBs change our understanding of evolution, including evolution of pathogen resistance to drugs, pathogen evasion of the immune system, and the evolution of cancers. © 2016 John Wiley & Sons, Inc. All rights reserved.