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The unstructured linker arms of MutL enable GATC site incision beyond roadblocks during initiation of DNA mismatch repair.


ABSTRACT: DNA mismatch repair (MMR) maintains genome stability through repair of DNA replication errors. In Escherichia coli, initiation of MMR involves recognition of the mismatch by MutS, recruitment of MutL, activation of endonuclease MutH and DNA strand incision at a hemimethylated GATC site. Here, we studied the mechanism of communication that couples mismatch recognition to daughter strand incision. We investigated the effect of catalytically-deficient Cas9 as well as stalled RNA polymerase as roadblocks placed on DNA in between the mismatch and GATC site in ensemble and single molecule nanomanipulation incision assays. The MMR proteins were observed to incise GATC sites beyond a roadblock, albeit with reduced efficiency. This residual incision is completely abolished upon shortening the disordered linker regions of MutL. These results indicate that roadblock bypass can be fully attributed to the long, disordered linker regions in MutL and establish that communication during MMR initiation occurs along the DNA backbone.

SUBMITTER: Mardenborough YSN 

PROVIDER: S-EPMC6902014 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The unstructured linker arms of MutL enable GATC site incision beyond roadblocks during initiation of DNA mismatch repair.

Mardenborough Yannicka S N YSN   Nitsenko Katerina K   Laffeber Charlie C   Duboc Camille C   Sahin Enes E   Quessada-Vial Audrey A   Winterwerp Herrie H K HHK   Sixma Titia K TK   Kanaar Roland R   Friedhoff Peter P   Strick Terence R TR   Lebbink Joyce H G JHG  

Nucleic acids research 20191201 22


DNA mismatch repair (MMR) maintains genome stability through repair of DNA replication errors. In Escherichia coli, initiation of MMR involves recognition of the mismatch by MutS, recruitment of MutL, activation of endonuclease MutH and DNA strand incision at a hemimethylated GATC site. Here, we studied the mechanism of communication that couples mismatch recognition to daughter strand incision. We investigated the effect of catalytically-deficient Cas9 as well as stalled RNA polymerase as roadb  ...[more]

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