Characterization of a Highly Conserved Binding Site of Mlh1 Required for Exonuclease I-Dependent Mismatch Repair

Dhérin, Claudine; Gueneau, Emeric; Francin, Mathilde; Nunez, Marcela; Miron, Simona; Liberti, Sascha Emilie; Rasmussen, Lene Juel; Zinn‐Justin, Sophie; Gilquin, Bernard; Charbonnier, Jean‐Baptiste; Boiteux, Serge

doi:10.1128/mcb.00945-08

Cited by 59 publications

(60 citation statements)

References 52 publications

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“…MutLa interacts with MutSa and MutSb to coordinate most MMR, and MutLg partners with MutSg to regulate meiotic crossover formation. In addition to being the common component of three MutL-like complexes, Mlh1 interacts with the Exo1 exonuclease during MMR (see below), the Ntg2 DNA N-glycosylase/lyase, and the Sgs1 helicase via a highly conserved binding site at its C terminus, which is referred to as S2 Dherin et al 2009). …”

Section: Mutl Homologsmentioning

confidence: 99%

“…The exo1D mutator phenotype reflects a role of Exo1 both during MMR and in the promotion of error-free damage bypass (Tran et al 2007). Mutating the Mlh1-interacting peptide of Exo1 or the S2 site of Mlh1 results in a modest MMR-dependent mutator phenotype, which is greatly enhanced when combined with hypomorphic mutations of MLH1 or PMS1 (Tran et al 2007;Dherin et al 2009). Interestingly, mutating the PIP box of Msh6, which by itself causes only a weak mutator phenotype, completely eliminates MutSa-dependent MMR in an exo1D background (Hombauer et al 2011a).…”

Section: Pcna Sliding Clampmentioning

confidence: 99%

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DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae

2013

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DNA repair mechanisms are critical for maintaining the integrity of genomic DNA, and their loss is associated with cancer predisposition syndromes. Studies in Saccharomyces cerevisiae have played a central role in elucidating the highly conserved mechanisms that promote eukaryotic genome stability. This review will focus on repair mechanisms that involve excision of a single strand from duplex DNA with the intact, complementary strand serving as a template to fill the resulting gap. These mechanisms are of two general types: those that remove damage from DNA and those that repair errors made during DNA synthesis. The major DNA-damage repair pathways are base excision repair and nucleotide excision repair, which, in the most simple terms, are distinguished by the extent of single-strand DNA removed together with the lesion. Mistakes made by DNA polymerases are corrected by the mismatch repair pathway, which also corrects mismatches generated when single strands of non-identical duplexes are exchanged during homologous recombination. In addition to the true repair pathways, the postreplication repair pathway allows lesions or structural aberrations that block replicative DNA polymerases to be tolerated. There are two bypass mechanisms: an error-free mechanism that involves a switch to an undamaged template for synthesis past the lesion and an error-prone mechanism that utilizes specialized translesion synthesis DNA polymerases to directly synthesize DNA across the lesion. A high level of functional redundancy exists among the pathways that deal with lesions, which minimizes the detrimental effects of endogenous and exogenous DNA damage.

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Section: Mutl Homologsmentioning

confidence: 99%

Section: Pcna Sliding Clampmentioning

confidence: 99%

DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae

2013

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“…MLH1 is also involved in recruitment of EXO1. 34 With the defective MLH1 gene, formation of the MMR complex is likely impaired in HCT116, and the MC13/Nick construct might become a substrate for repair through the EXO1-independent MMR mechanism, proposed to use enzymes involved in synthesis of Okazaki fragments. Thus, we hypothesize that this setting reflects strand displacement synthesis, with PCNA loaded at a nick and forming a complex with Pol d. Here, the mismatch-creating stop codon is removed through formation of a flap subsequently cleaved as described in Okazaki fragment maturation and EXO1-independent MMR.…”

Section: Efficiency Of Mmr Increases In Cells Exposed To a Histone Dementioning

confidence: 99%

Acetylation regulates DNA repair mechanisms in human cells

2016

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The p300-mediated acetylation of enzymes involved in DNA repair and replication has been previously shown to stimulate or inhibit their activities in reconstituted systems. To explore the role of acetylation on DNA repair in cells we constructed plasmid substrates carrying inactivating damages in the EGFP reporter gene, which should be repaired in cells through DNA mismatch repair (MMR) or base excision repair (BER) mechanisms. We analyzed efficiency of repair within these plasmid substrates in cells exposed to deacetylase and acetyltransferase inhibitors, and also in cells deficient in p300 acetyltransferase. Our results indicate that protein acetylation improves DNA mismatch repair in MMR-proficient HeLa cells and also in MMR-deficient HCT116 cells. Moreover, results suggest that stimulated repair of mismatches in MMR-deficient HCT116 cells is done though a strand-displacement synthesis mechanism described previously for Okazaki fragments maturation and also for the EXOI-independent pathway of MMR. Loss of p300 reduced repair of mismatches in MMR-deficient cells, but did not have evident effects on BER mechanisms, including the long patch BER pathway. Hypoacetylation of the cells in the presence of acetyltransferase inhibitor, garcinol generally reduced efficiency of BER of 8-oxoG damage, indicating that some steps in the pathway are stimulated by acetylation.

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“…As discussed above, MutLa creates additional loading sites for EXO1; the two enzymes apparently work in concert in S. cerevisiae, because EXO1 was shown to interact with MLH1 via a highly conserved motif in the latter polypeptide, and mutation of this site gave rise to a phenotype resembling an EXO1 hypomorph (Dherin et al 2009). However, in the absence of EXO1, a limited amount of MMR could still be detected in vitro, and this reaction required the MutLa endonuclease and a DNA polymerase.…”

Section: Degradation Of the Error-containing Strandmentioning

confidence: 99%

Postreplicative Mismatch Repair

Jiricny

2013

Cold Spring Harbor Perspectives in Biology

288

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The mismatch repair (MMR) system detects non-Watson -Crick base pairs and strand misalignments arising during DNA replication and mediates their removal by catalyzing excision of the mispair-containing tract of nascent DNA and its error-free resynthesis. In this way, MMR improves the fidelity of replication by several orders of magnitude. It also addresses mispairs and strand misalignments arising during recombination and prevents synapses between nonidentical DNA sequences. Unsurprisingly, MMR malfunction brings about genomic instability that leads to cancer in mammals. But MMR proteins have recently been implicated also in other processes of DNA metabolism, such as DNA damage signaling, antibody diversification, and repair of interstrand cross-links and oxidative DNA damage, in which their functions remain to be elucidated. This article reviews the progress in our understanding of the mechanism of replication error repair made during the past decade.

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Characterization of a Highly Conserved Binding Site of Mlh1 Required for Exonuclease I-Dependent Mismatch Repair

Abstract: Mlh1 is an essential factor of mismatch repair (MMR) and meiotic recombination. It interacts through its

Cited by 59 publications

References 52 publications

DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae

DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae

Acetylation regulates DNA repair mechanisms in human cells

Postreplicative Mismatch Repair

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