A Defined Human System That Supports Bidirectional Mismatch-Provoked Excision

Dzantiev, Leonid; Constantin, Nicoleta; Genschel, Jochen; Iyer, Ravi; Burgers, Peter M.; Modrich, Paul

doi:10.1016/j.molcel.2004.06.016

Cited by 210 publications

(327 citation statements)

References 51 publications

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“…This finding coincided with an earlier report that PCNA was required for MMR prior to replacement strand synthesis [7]. The possibility of a cryptic 3′ → 5′ hydrolytic activity in ExoI was raised [6], but no evidence was found. Finally, with purified MutSα, MutLα, RFC and PCNA, an endonuclease activity, which weakly but specifically incises the discontinuous strand in a mismatchcontaining heteroduplex, was detected and located in MutLα [4].…”

supporting

confidence: 89%

“…Genschel and Modrich, using mammalian cell extracts, showed that ExoI and MutSα are essential for mismatch removal from a 5′ strand break, but MutLα is required in addition when the break is 3′ to the mismatch [5]. Later, in vitro reconstitution of human MMR with purified proteins revealed the additional requirements for the sliding clamp PCNA and its loader RFC for 3′ directed MMR [6]. This finding coincided with an earlier report that PCNA was required for MMR prior to replacement strand synthesis [7].…”

mentioning

confidence: 99%

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Human MutLα: The jack of all trades in MMR is also an endonuclease

Yang

2007

DNA Repair

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SummaryRecently, Paul Modrich's group reported the discovery of an intrinsic endonuclease activity for human MutLα. This breakthrough provides a satisfactory answer to the longstanding puzzle of a missing nuclease activity in human mismatch repair and will undoubtedly lead to new investigations of DNA repair and replication. Here, the implications of this exciting new finding are discussed in the context of mismatch repair in E. coli and humans.Correction of replication errors by mismatch repair (MMR) has long been recognized as critical for genomic stability. Inactivation of MMR in humans has been implicated in > 90% of hereditary nonpolyposis colorectal cancers [1]. Like every DNA repair process, the success of MMR depends on two essential steps: lesion detection and removal. MMR is unique in two aspects. The targets of repair are normal rather than damaged nucleotides, and nucleotide removal has to be specific to the newly synthesized daughter strand and not the template. E. coli MMR is the best understood and has been fully reconstituted in vitro using a dozen or so purified proteins [2,3]. Recognition of a normal nucleotide that fails to make a Watson-Crick base pair in a DNA duplex is accomplished by the MutS protein. The strand specificity of MMR in E. coli is conferred by a sequence and methylation specific endonuclease MutH, which makes an incision (nick) 5′ to a GATC sequence in the unmethylated daughter strand. The GATC sequence may be several hundred base pairs from the mismatch on either the 5′ or 3′ side (Fig. 1A). The direction of daughter strand removal is strongly biased towards the shorter track between the nick and mismatch in a circular genome. The degradation of hundreds to a thousand nucleotides is carried out by one of several exonucleases with 5′ → 3′ or 3′-gt; 5′ polarity in the presence of the UvrD helicase and the single strand binding protein SSB. An additional central player in MMR is MutL, a molecular matchmaker that mediates proteinprotein interactions and coordinates mismatch recognition with strand incision and degradation (Fig. 1A).The MMR pathway is conserved from E. coli to humans [3]. The essential proteins known to specialize in human MMR are so far limited to MutS and MutL homologs and a 5′ → 3′ exonuclease, ExoI. Eukaryotic MutS and MutL are heterodimers of homologous subunits as opposed to homodimers in bacteria. Human MutSα consists of MSH2 and MSH6, and MutLα consists of MLH1 and PMS2. A strand-specific endonuclease that nicks the daughter strand, like MutH in E. coli, is missing in all eukaryotes and in many bacteria. It is thusCorrespondence and request for material should be addressed to W.Y. e-mail: Wei.Yang@nih.gov phone: (301), 402-4645, fax: (301) 496-0201. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its...

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supporting

confidence: 89%

mentioning

confidence: 99%

Human MutLα: The jack of all trades in MMR is also an endonuclease

Yang

2007

DNA Repair

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“…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).…”

Section: Mutation Avoidance and Post-replication Repairmentioning

confidence: 99%

“…A second puzzle is the absence of a requirement for a 3′-5′ exonuclease in reconstituted 3′-nick-directed MMR reactions and a surprising requirement for EXO1, a 5′-3′ exonuclease, in the 3′-directed reaction (Genschel et al, 2002;Dzantiev et al, 2004). How is the excision step being carried out in this case?…”

Section: A Ternary Complexmentioning

confidence: 99%

“…A weak interaction between yeast and human MutLα and PCNA has been reported and mutation of the putative PIP motif in MLH1 confers a mutator phenotype (Lee and Alani, 2006;Dzantiev et al, 2004;Umar et al, 1996). PCNA also interacts with EXO1 and has important functions in the excision step of MMR (Dzantiev et al, 2004;Nielsen et al, 2004). Understanding how the various proteins involved in MMR gain orderly access to newly replicated DNA remains an important goal.…”

Section: A Ternary Complexmentioning

confidence: 99%

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DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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A Defined Human System That Supports Bidirectional Mismatch-Provoked Excision

Cited by 210 publications

References 51 publications

Human MutLα: The jack of all trades in MMR is also an endonuclease

Human MutLα: The jack of all trades in MMR is also an endonuclease

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Mechanismen der Fehlpaarungsreparatur in E. coli und im Menschen (Nobel‐Aufsatz)

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