title: Noncanonical mismatch repair as a source of genomic instability in human cells.
abstract: Mismatch 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.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. diaz@imcr.uzh.ch
authors.forename: Javier
authors.initials: J
authors.lastname: Peña-Diaz
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bregenhorn
authors.forename: Medini
authors.initials: M
authors.lastname: Ghodgaonkar
authors.forename: Cindy
authors.initials: C
authors.lastname: Follonier
authors.forename: Mariela
authors.initials: M
authors.lastname: Artola-Borán
authors.forename: Dennis
authors.initials: D
authors.lastname: Castor
authors.forename: Massimo
authors.initials: M
authors.lastname: Lopes
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Sartori
authors.forename: Josef
authors.initials: J
authors.lastname: Jiricny
mesh_terms: D002478:Cells, Cultured; D053843:DNA Mismatch Repair / Q000235:genetics*; D004261:DNA Replication; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism
chemical_list: D018809:Proliferating Cell Nuclear Antigen