Linker domain function predicts pathogenic MLH1 missense variants

The pathogenic consequences of 369 unique human HsMLH1 missense variants has been hampered by the lack of a detailed function in mismatch repair (MMR). Here single-molecule images show that HsMSH2-HsMSH6 provides a platform for HsMLH1-HsPMS2 to form a stable sliding clamp on mismatched DNA. The mech...

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Detalles Bibliográficos
Autores principales: London, James, Martín-López, Juana, Yang, Inho, Liu, Jiaquan, Lee, Jong-Bong, Fishel, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Biological Sciences
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936337/
https://www.ncbi.nlm.nih.gov/pubmed/33619096
http://dx.doi.org/10.1073/pnas.2019215118
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author London, James
Martín-López, Juana
Yang, Inho
Liu, Jiaquan
Lee, Jong-Bong
Fishel, Richard
author_facet London, James
Martín-López, Juana
Yang, Inho
Liu, Jiaquan
Lee, Jong-Bong
Fishel, Richard
author_sort London, James
collection PubMed
description The pathogenic consequences of 369 unique human HsMLH1 missense variants has been hampered by the lack of a detailed function in mismatch repair (MMR). Here single-molecule images show that HsMSH2-HsMSH6 provides a platform for HsMLH1-HsPMS2 to form a stable sliding clamp on mismatched DNA. The mechanics of sliding clamp progression solves a significant operational puzzle in MMR and provides explicit predictions for the distribution of clinically relevant HsMLH1 missense mutations.
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spelling pubmed-79363372021-03-11 Linker domain function predicts pathogenic MLH1 missense variants London, James Martín-López, Juana Yang, Inho Liu, Jiaquan Lee, Jong-Bong Fishel, Richard Proc Natl Acad Sci U S A Biological Sciences The pathogenic consequences of 369 unique human HsMLH1 missense variants has been hampered by the lack of a detailed function in mismatch repair (MMR). Here single-molecule images show that HsMSH2-HsMSH6 provides a platform for HsMLH1-HsPMS2 to form a stable sliding clamp on mismatched DNA. The mechanics of sliding clamp progression solves a significant operational puzzle in MMR and provides explicit predictions for the distribution of clinically relevant HsMLH1 missense mutations. National Academy of Sciences 2021-03-02 2021-02-22 /pmc/articles/PMC7936337/ /pubmed/33619096 http://dx.doi.org/10.1073/pnas.2019215118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
London, James
Martín-López, Juana
Yang, Inho
Liu, Jiaquan
Lee, Jong-Bong
Fishel, Richard
Linker domain function predicts pathogenic MLH1 missense variants
title Linker domain function predicts pathogenic MLH1 missense variants
title_full Linker domain function predicts pathogenic MLH1 missense variants
title_fullStr Linker domain function predicts pathogenic MLH1 missense variants
title_full_unstemmed Linker domain function predicts pathogenic MLH1 missense variants
title_short Linker domain function predicts pathogenic MLH1 missense variants
title_sort linker domain function predicts pathogenic mlh1 missense variants
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936337/
https://www.ncbi.nlm.nih.gov/pubmed/33619096
http://dx.doi.org/10.1073/pnas.2019215118
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