The selection process of licensing a DNA mismatch for repair

Rafael Fernandez-Leiro*, Doreth Bhairosing-Kok, Vladislav Kunetsky, Charlie Laffeber, Herrie H. Winterwerp, Flora Groothuizen, Alexander Fish, Joyce H.G. Lebbink, Peter Friedhoff, Titia K. Sixma*, Meindert H. Lamers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)
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DNA mismatch repair detects and removes mismatches from DNA by a conserved mechanism, reducing the error rate of DNA replication by 100- to 1,000-fold. In this process, MutS homologs scan DNA, recognize mismatches and initiate repair. How the MutS homologs selectively license repair of a mismatch among millions of matched base pairs is not understood. Here we present four cryo-EM structures of Escherichia coli MutS that provide snapshots, from scanning homoduplex DNA to mismatch binding and MutL activation via an intermediate state. During scanning, the homoduplex DNA forms a steric block that prevents MutS from transitioning into the MutL-bound clamp state, which can only be overcome through kinking of the DNA at a mismatch. Structural asymmetry in all four structures indicates a division of labor between the two MutS monomers. Together, these structures reveal how a small conformational change from the homoduplex- to heteroduplex-bound MutS acts as a licensing step that triggers a dramatic conformational change that enables MutL binding and initiation of the repair cascade.

Original languageEnglish
Pages (from-to)373-381
Number of pages9
JournalNature Structural and Molecular Biology
Issue number4
Publication statusPublished - Apr 2021

Bibliographical note

Funding Information:
All cryo-EM data were collected at the LMB cryo-EM facility. We thank C. Savva for cryo-EM support; and J. Grimmett, T. Darling, J. L. Fernández and P. Reviriego for IT support. This work has been supported by a UK Medical Research Council grant U105197143 and LUMC Research Fellowship to M.H.L.; the Oncode Institute, NWO-TOP 714.016.002 and NWO-Gravity to T.K.S.; a Spanish Ministry of Economy and Competitiveness Grant BFU2017-87316 to R.F.L.; NWO-Gravity and the Oncode Institute to J.H.G.L.; and European Community’s Horizon2020 Marie Skłodowska Curie grant [722433] to P.F.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.


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