MutL binds to 3' resected DNA ends and blocks DNA polymerase access

Alessandro Borsellini, Joyce H.G. Lebbink, Meindert H. Lamers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
24 Downloads (Pure)

Abstract

DNA mismatch repair removes mis-incorporated bases after DNA replication and reduces the error rate a 100-1000-fold. After recognition of a mismatch, a large section of up to a thousand nucleotides is removed from the daughter strand followed by re-synthesis. How these opposite activities are coordinated is poorly understood. Here we show that the Escherichia coli MutL protein binds to the 3' end of the resected strand and blocks access of Pol I and Pol III. The cryo-EM structure of an 85-kDa MutL-DNA complex, determined to 3.7 Å resolution, reveals a unique DNA binding mode that positions MutL at the 3' end of a primer-template, but not at a 5' resected DNA end or a blunt DNA end. Hence, our work reveals a novel role for MutL in the final stages of mismatch repair by preventing premature DNA synthesis during removal of the mismatched strand.

Original languageEnglish
Pages (from-to)6224-6234
Number of pages11
JournalNucleic Acids Research
Volume50
Issue number11
DOIs
Publication statusPublished - 24 Jun 2022

Bibliographical note

Funding Information:
LUMC Research Fellowship (to M.H.L.); European Community's Horizon 2020 Innovative Training Network [722433 to M.H.L., J.H.G.L.]; gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO), part of the Oncode Institute, which is partly financed by the Dutch Cancer Society; access to NeCEN was supported by the Netherlands Electron Microscopy Infrastructure (NEMI), [184.034.014] of the National Roadmap for Large-Scale Research Infrastructure of the Dutch Research Council (NWO). Funding for open access charge: European Community's Horizon 2020 Innovative Training Network [to M.H.L.].

Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

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