Noncanonical Mismatch Repair as a Source of Genomic Instability in Human Cells
2012; Elsevier BV; Volume: 47; Issue: 5 Linguagem: Inglês
10.1016/j.molcel.2012.07.006
ISSN1097-4164
AutoresJavier Peña-Dı́az, Stephanie Bregenhorn, Medini M. Ghodgaonkar, Cindy Follonier, Mariela Artola-Borán, Dennis Castor, Massimo Lopes, Alessandro A. Sartori, Josef Jiricny,
Tópico(s)Chromosomal and Genetic Variations
ResumoSummaryMismatch repair (MMR) is a key antimutagenic process that increases the fidelity of DNA replication and recombination. Yet genetic experiments showed that MMR is required for antibody maturation, a process during which the immunoglobulin loci of antigen-stimulated B cells undergo extensive mutagenesis and rearrangements. In an attempt to elucidate the mechanism underlying the latter events, we set out to search for conditions that compromise MMR fidelity. Here, we describe noncanonical MMR (ncMMR), a process in which the MMR pathway is activated by various DNA lesions rather than by mispairs. ncMMR is largely independent of DNA replication, lacks strand directionality, triggers PCNA monoubiquitylation, and promotes recruitment of the error-prone polymerase-η to chromatin. Importantly, ncMMR is not limited to B cells but occurs also in other cell types. Moreover, it contributes to mutagenesis induced by alkylating agents. Activation of ncMMR may therefore play a role in genomic instability and cancer.Highlights•ncMMR is a variant of mismatch repair that is activated by a variety of lesions•ncMMR lacks strand bias and induces PCNA monoubiquitylation•ncMMR brings about recruitment of error-prone polymerase(s) to chromatin•ncMMR promotes mutagenesis outside of S phase
Referência(s)