New insights and challenges in mismatch repair: getting over the chromatin hurdle.
DNA mismatch repair (MMR) maintains genome stability primarily by repairing DNA replication-associated mispairs. Because loss of MMR function increases the mutation frequency genome-wide, defects in this pathway predispose affected individuals to cancer. The genes encoding essential eukaryotic MMR activities have been identified, as the recombinant proteins repair 'naked' heteroduplex DNA in vitro. However, the reconstituted system is inactive on nucleosome-containing heteroduplex DNA, and it is not understood how MMR occurs in vivo. Recent studies suggest that chromatin organization, nucleosome assembly/disassembly factors and histone modifications regulate MMR in eukaryotic cells, but the complexity and importance of the interaction between MMR and chromatin remodeling has only recently begun to be appreciated. This article reviews recent progress in understanding the mechanism of eukaryotic MMR in the context of chromatin structure and dynamics, considers the implications of these recent findings and discusses unresolved questions and challenges in understanding eukaryotic MMR.
Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA. Electronic address: gmli@uky.edu.
Guo-Min
GM
Li
D002843:Chromatin / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D053843:DNA Mismatch Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D009692:Nucleic Acid Heteroduplexes / Q000235:genetics; D009707:Nucleosomes / Q000235:genetics
D002843:Chromatin; D009692:Nucleic Acid Heteroduplexes; D009707:Nucleosomes
Chromatin; Genetic instability; H3K36me3; Histone modification; Mismatch repair