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

doi:10.1038/s41594-021-00577-7

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 journal › Article › Academic › peer-review

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Abstract

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 language	English
Pages (from-to)	373-381
Number of pages	9
Journal	Nature Structural and Molecular Biology
Volume	28
Issue number	4
DOIs	https://doi.org/10.1038/s41594-021-00577-7
Publication status	Published - 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 CGC.nl to T.K.S.; a Spanish Ministry of Economy and Competitiveness Grant BFU2017-87316 to R.F.L.; NWO-Gravity CGC.nl 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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The selection process of licensing a DNA mismatch for repairFinal published version, 7.18 MBLicence: CC BY

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title = "The selection process of licensing a DNA mismatch for repair",

abstract = "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.",

author = "Rafael Fernandez-Leiro and Doreth Bhairosing-Kok and Vladislav Kunetsky and Charlie Laffeber and Winterwerp, \{Herrie H.\} and Flora Groothuizen and Alexander Fish and Lebbink, \{Joyce H.G.\} and Peter Friedhoff and Sixma, \{Titia K.\} and Lamers, \{Meindert H.\}",

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. Fern{\'a}ndez 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 CGC.nl to T.K.S.; a Spanish Ministry of Economy and Competitiveness Grant BFU2017-87316 to R.F.L.; NWO-Gravity CGC.nl and the Oncode Institute to J.H.G.L.; and European Community{\textquoteright}s Horizon2020 Marie Sk{\l}odowska Curie grant [722433] to P.F. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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The selection process of licensing a DNA mismatch for repair

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