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

Masayoshi Honda; Yusuke Okuno; Sarah R Hengel; Juana V Martín-López; Christopher P Cook; Ravindra Amunugama; Randal J Soukup; Shyamal Subramanyam; Richard Fishel; Maria Spies

doi:10.1073/pnas.1312988111

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

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

Masayoshi Honda, Yusuke Okuno, Sarah R Hengel, Juana V Martín-López, Christopher P Cook, Ravindra Amunugama, Randal J Soukup, Shyamal Subramanyam, Richard Fishel and Maria Spies

Proceedings of the National Academy of Sciences - PNAS, Vol.111(3), pp.E316-E325

PNAS Plus

01/21/2014

DOI: 10.1073/pnas.1312988111

PMCID: PMC3903253

PMID: 24395779

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Abstract

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 D-loop 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.

Biological Sciences

single-molecule

PNAS Plus

homologous recombination

homeologous recombination

total internal reflection fluorescence microscopy

mismatch DNA repair

Details

Title: Subtitle: Mismatch repair protein hMSH2–hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate
Creators: Masayoshi Honda - Department of Biochemistry
Yusuke Okuno - Department of Biochemistry
Sarah R Hengel - Department of Biochemistry
Juana V Martín-López - Department of Molecular Virology, Immunology, and Medical Genetics
Christopher P Cook - Department of Molecular Virology, Immunology, and Medical Genetics
Ravindra Amunugama - Department of Molecular Virology, Immunology, and Medical Genetics
Randal J Soukup - Department of Molecular Virology, Immunology, and Medical Genetics
Shyamal Subramanyam - Department of Biochemistry
Richard Fishel - Department of Molecular Virology, Immunology, and Medical Genetics
Maria Spies - Department of Biochemistry
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.111(3), pp.E316-E325
Series: PNAS Plus
DOI: 10.1073/pnas.1312988111
PMID: 24395779
PMCID: PMC3903253
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Alternative title: hMSH2-MSH6 recognizes mismatches within the D-loop
Language: English
Date published: 01/21/2014
Academic Unit: Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984025399002771

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