The multifaceted mismatch-repair system

Abstract

By removing biosynthetic errors from newly synthesized DNA, mismatch repair (MMR) improves the fidelity of DNA replication by several orders of magnitude. Loss of MMR brings about a mutator phenotype, which causes a predisposition to cancer. But MMR status also affects meiotic and mitotic recombination, DNA-damage signalling, apoptosis and cell-type-specific processes such as class-switch recombination, somatic hypermutation and triplet-repeat expansion. This article reviews our current understanding of this multifaceted DNA-repair system in human cells.

DNA mismatch repair: Molecular mechanism, cancer, and ageing

“…1 and discussion below), and reconstitutions in the Li and Modrich laboratories of MMR reactions from purified proteins possess many of the key features associated with MMR in vivo (Constantin et al, 2005;Dzantiev et al, 2004;Zhang et al, 2005). These studies were predicated on a large body of earlier work that identified individual components from active fractions of cell extracts and characterized partial reactions (reviewed in Jiricny, 2006). Zhang et al (2005) have demonstrated MMR of a G-T mismatch in 5′-directed repair reactions containing MutSα, MutLα, RPA, EXO1, PCNA, RFC, HMGB1, DNA polymerase δ, and DNA ligase I (Yuan et al, 2004).…”

“…Since discrimination between mismatched DNA and perfectly paired DNA is not large, most commonly no more than two orders of magnitude (reviewed in Jiricny, 2006;Kunkel and Erie, 2005;Schofield and Hsieh, 2003), the issue of finding a mismatch is not trivial. Total internal reflection fluorescence microscopy of yMSH2-MSH6 reveals that the protein travels along undamaged DNA duplexes via ID diffusion (Gorman et al, 2007).…”

“…The MutS proteins not only recognize mismatches arising from replication errors but also recognize mismatches involving damaged or modified bases that result from exposure of cells to certain DNA damaging agents (reviewed in Jiricny, 2006). These include O 6 methylguanine (O 6 meG) resulting from modification by S N 1 alkylators, 8-oxoguanine, halogenated pyrimidines such as 5-fluorouracil (FdU), adducts from environmental carcinogens like benzo [c]phenanthrene dihydrodiol epoxide (Wu et al, 2003a), UV photoproducts , and cisplatin adducts.…”

“…The cell cycle arrest induced by treatment of cells with low doses of MNNG requires the ataxia telangiectasia and Rad3-related (ATR) kinase, whose downstream target is the checkpoint kinase Chk1 (Jiricny, 2006). Interestingly, cell cycle arrest only ensues in the second cell cycle after exposure to MNNG (Kaina, 2004;Stojic et al, 2004).…”

“…We review what is known concerning the molecular mechanism of MMR, its role in DNA damage signalling, and its relationship to cancer and ageing. The recent literature is emphasized; for more comprehensive discussions, please see Harfe and Jinks-Robertson (2000), Jiricny (2006), Kunkel and Erie (2005), Modrich (2006), Schofield and Hsieh (2003).…”