Nucleosome Remodeling by hMSH2-hMSH6

Javaid, Sarah; Manohar, Mridula; Punja, Nidhi; Mooney, Alex M.; Ottesen, Jennifer J.; Poirier, Michael G.; Fishel, Richard

doi:10.1016/j.molcel.2009.12.010

Cited by 62 publications

(92 citation statements)

References 39 publications

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“…1B; (21). It is important to be aware that during the 10-min cross-linking in the presence of magnesium, there is likely to be significant but slow hydrolysis of the [␥- 35 (34). For example, we observe a decrease in cross-linking affinity for both WT subunits compared with experiments in the absence of magnesium (Fig.…”

Section: Resultsmentioning

confidence: 71%

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Human MSH2 (hMSH2) Protein Controls ATP Processing by hMSH2-hMSH6

Heinen

Cyr

Cook

et al. 2011

Journal of Biological Chemistry

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Background:The hMSH2-hMSH6 heterodimer must coordinate mismatch binding with dual site adenosine nucleotide processing. Results: An hMSH2-magnesium-ADP complex inhibits ATP hydrolysis by both the hMSH2 and hMSH6 subunits. Conclusion: hMSH2 regulates adenosine nucleotide processing by the hMSH2-hMSH6 mismatch recognition heterodimer. Significance: Understanding the molecular mechanism of hMSH2-hMSH6 function is crucial for elucidating the role of the mismatch repair pathway in human tumorigenesis.

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Section: Resultsmentioning

confidence: 71%

“…S1A and Table 1) (34). In general, the [␥- 35 S]ATP filter binding (K D ) and cross-link affinity (S 0.5 ) in the presence or absence of magnesium appear largely equivalent (compare Fig.…”

Section: Resultsmentioning

confidence: 84%

Human MSH2 (hMSH2) Protein Controls ATP Processing by hMSH2-hMSH6

Heinen

Cyr

Cook

et al. 2011

Journal of Biological Chemistry

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“…Additional factors such as RAD54 might be necessary to dissociate the RAD51 NPF from the newly formed heteroduplex dsDNA (55). Alternatively, multiple events of hMSH2-hMSH6 loading may enhance disassembly of the dynamic RAD51 filament by a mechanism similar to hMSH2-hMSH6-mediated nucleosome remodeling (56).…”

Section: Discussionmentioning

confidence: 99%

Mismatch repair protein hMSH2–hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate

Honda

Okuno

Hengel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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High fidelity homologous DNA recombination depends on mismatch repair (MMR), which antagonizes recombination between divergent sequences by rejecting heteroduplex DNA containing excessive nucleotide mismatches. The hMSH2-hMSH6 heterodimer is the first responder in postreplicative MMR and also plays a prominent role in heteroduplex rejection. Whether a similar molecular mechanism underlies its function in these two processes remains enigmatic. We have determined that hMSH2-hMSH6 efficiently recognizes mismatches within a D-loop recombination initiation intermediate. Mismatch recognition by hMSH2-hMSH6 is not abrogated by human replication protein A (HsRPA) bound to the displaced single-stranded DNA (ssDNA) or by HsRAD51. In addition, ATP-bound hMSH2-hMSH6 sliding clamps that are essential for downstream MMR processes are formed and constrained within the heteroduplex region of the D-loop. Moreover, the hMSH2-hMSH6 sliding clamps are stabilized on the Dloop by HsRPA bound to the displaced ssDNA. Our findings reveal similarities and differences in hMSH2-hMSH6 mismatch recognition and sliding-clamp formation between a D-loop recombination intermediate and linear duplex DNA.

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“…An alternative explanation could be that nucleosomes present no barrier to MMR (12). To test this possibility, we preincubated the substrates with the MMR-deficient LoVo extracts for 10 min prior to adding MutSα.…”

Section: Caf-1 Does Not Overcome Mmr-dependent Inhibition Of Nucleosomementioning

confidence: 99%

Interplay between mismatch repair and chromatin assembly

Schöpf

Bregenhorn

Quivy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Single strand nicks and gaps in DNA have been reported to increase the efficiency of nucleosome loading mediated by chromatin assembly factor 1 (CAF-1). However, on mismatch-containing substrates, these strand discontinuities are utilized by the mismatch repair (MMR) system as loading sites for exonuclease 1, at which degradation of the error-containing strand commences. Because packaging of DNA into chromatin might inhibit MMR, we were interested to learn whether chromatin assembly is differentially regulated on heteroduplex and homoduplex substrates. We now show that the presence of a mismatch in a nicked plasmid substrate delays nucleosome loading in human cell extracts. Our data also suggest that, once the mismatch is removed, repair of the single-stranded gap is accompanied by efficient nucleosome loading. We postulated that the balance between MMR and chromatin assembly might be governed by proliferating cell nuclear antigen (PCNA), the processivity factor of replicative DNA polymerases, which is loaded at DNA termini and which interacts with the MSH6 subunit of the mismatch recognition factor MutSα, as well as with CAF-1. We now show that this regulation might be more complex; MutSα and CAF-1 interact not only with PCNA, but also with each other. In vivo this interaction increases during S-phase and may be controlled by the phosphorylation status of the p150 subunit of CAF-1. MMR has evolved to process mismatches arising during replication or recombination (1, 2). That its malfunction leads to cancer (3) bears witness to the importance of its role in the maintenance of genomic stability. In eukaryotes, mismatch repair (MMR) is initiated by the binding of MutSα, a heterodimer of MSH2 and MSH6, to non-Watson-Crick base pairs in DNA. Exchange of ADP for ATP then converts MutSα into a sliding clamp, which diffuses along the DNA contour, possibly together with a heterodimer of MLH1/PMS2 named MutLα, in search of free DNA termini that serve as initiation sites for exonuclease 1-catalyzed degradation of the error-containing DNA strand (1, 2).In mammalian cells, free termini are generally marked by PCNA, which helps orchestrate replication and repair DNA synthesis through interactions with key players of DNA metabolism, including MSH6 and chromatin assembly factor 1 (CAF-1) (4). The latter complex, composed of p150, p60, and p48 subunits (5), promotes rapid assembly of nucleosomes on newly replicated DNA (6).Nucleosome loading causes supercoiling, which compacts the genome and increases its stability, but which makes DNA less accessible to metabolic processes. Thus, during nucleotide excision repair, efficient processing of UV-induced DNA damage requires chromatin remodeling (7, 8) and CAF-1-mediated chromatin reassembly upon repair completion (9). Whether similar transactions take place during MMR is unknown. As the sliding function of MutSα was reported to be blocked by nucleosomes (10, 11), albeit not in all sequence contexts (12), we argued that mismatches arising during replication would have to be repaired ...

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Nucleosome Remodeling by hMSH2-hMSH6

Cited by 62 publications

References 39 publications

Human MSH2 (hMSH2) Protein Controls ATP Processing by hMSH2-hMSH6

Human MSH2 (hMSH2) Protein Controls ATP Processing by hMSH2-hMSH6

Mismatch repair protein hMSH2–hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate

Interplay between mismatch repair and chromatin assembly

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