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Nucleic Acids Res. 2019 Dec 16;47(22):11667-11680. doi: 10.1093/nar/gkz834.

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

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Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
Institut Jacques Monod, CNRS, UMR7592, University Paris Diderot, Sorbonne Paris Cité, F-75205 Paris, France.
Oncode Institute, the Netherlands.
Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Institute for Biochemistry, Justus-Liebig University, Giessen, Germany.
Ecole Normale Supérieure, Institut de Biologie de l'Ecole Normale Superieure, CNRS, INSERM, PSL Research University, 75005 Paris, France.
Programme "Equipe Labellisée", Ligue Nationale contre le Cancer.
Department of Radiation Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands.


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.

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