Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA

Nielsen, Finn Cilius; Jäger, Anne Charlotte; Lützen, Anne; Bundgaard, Jens R.; Rasmussen, Lene Juel

doi:10.1038/sj.onc.1207265

Cited by 68 publications

(70 citation statements)

References 73 publications

(81 reference statements)

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“…A model for the termination of excision involves the inhibition of EXO1 activity by MutSα and MutLα once the mismatch has been removed and displacement from DNA of EXO1 by RPA. Consistent with these observations, MutSα and MutLα can inhibit EXO1 activity in the absence of a mismatch, but not in its presence (Nielsen et al, 2004).…”

Section: A Ternary Complexsupporting

confidence: 74%

“…EXO1 may also have multiple roles in MMR as genetic evidence supports a structural or chaperone role for EXO1 in the formation and/or stabilization of MMR protein complexes in addition to its catalytic role as an exonuclease (Amin et al, 2001;Nielsen et al, 2004;Tishkoff et al, 1997;Tran et al, 2007). Recent studies of EXO1 function in telomerase dysfunctional mTerc −/− mice reveal that the exonuclease domain of EXO1 has important roles in inducing DNA damage signalling, cell cycle arrest, and apoptosis in telomere-dysfunctional mice presumably due to the formation of ssDNA .…”

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

387

359

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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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Section: A Ternary Complexsupporting

confidence: 74%

Section: A Ternary Complexmentioning

confidence: 99%

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

387

359

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“…Structure-function studies have delineated modular domains of Exo1p (see Figure 2A) [12,19,[42][43][44][45]. Functionally, Exo1p can be split into NH 2 -and COOH-terminal halves, required for nuclease and protein-protein interaction activities [19,42,45], respectively.…”

Section: Mapping Separate Exo1p "Prr" and "Mmr" Domainsmentioning

confidence: 99%

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

et al. 2007

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Replication forks stall at DNA lesions or as a result of an unfavorable replicative environment. These fork stalling events have been associated with recombination and gross chromosomal rearrangements. Recombination and fork bypass pathways are the mechanisms accountable for restart of stalled forks. An important lesion bypass mechanism is the highly conserved postreplication repair (PRR) pathway that is composed of error-prone translesion and error-free bypass branches. EXO1 codes for a Rad2p family member nuclease that has been implicated in a multitude of eukaryotic DNA metabolic pathways that include DNA repair, recombination, replication, and telomere integrity. In this report, we show EXO1 functions in the MMS2 error-free branch of the PRR pathway independent of the role of EXO1 in DNA mismatch repair (MMR). Consistent with the idea that EXO1 functions independently in two separate pathways, we defined a domain of Exo1p required for PRR distinct from those required for interaction with MMR proteins. We then generated a point mutant exo1 allele that was defective for the function of Exo1p in MMR due to disrupted interaction with Mlh1p, but still functional for PRR. Lastly, by using a compound exo1 mutant that was defective for interaction with Mlh1p and deficient for nuclease activity, we provide further evidence that Exo1p plays both structural and catalytic roles during MMR.

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“…Consistent with its role in nicking abasic sites, Mre11, but not the ubiquitous APE, is enriched on V(D)J DNA of hypermutating B cells and the MRN complex promotes SHM (Larson et al, 2005;Yabuki et al, 2005), suggesting that at least some SHM MMR is initiated by this complex. Both Exo I and MRN bind to PCNA (Maser et al, 2001;Nielsen et al, 2004), indicating that PCNA is also involved in DNA strand excision.…”

Section: Error-prone Mmr Amplifies Mutations In the Mutasomementioning

confidence: 99%