Human mismatch repair protein MSH6 contains a PWWP domain that targets double stranded DNA |
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Authors: | Laguri Cédric Duband-Goulet Isabelle Friedrich Nikolas Axt Marianne Belin Pascal Callebaut Isabelle Gilquin Bernard Zinn-Justin Sophie Couprie Joël |
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Affiliation: | CEA Laboratoire de Biologie Structurale et Radiobiologie, iBiTec-Saclay, 91191 Gif sur Yvette, France. |
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Abstract: | The eukaryotic mismatch repair (MMR) protein MSH6 exhibits a core region structurally and functionally similar to bacterial MutS. However, it possesses an additional N-terminal region (NTR), comprising a PCNA binding motif, a large region of unknown function and a nonspecific DNA binding fragment. Yeast NTR was recently described as an extended tether between PCNA and the core of MSH6 . In contrast, we show that human NTR presents a globular PWWP domain in the region of unknown function. We demonstrate that this PWWP domain binds double-stranded DNA, without any preference for mismatches or nicks, whereas its apparent affinity for single-stranded DNA is about 20 times lower. The S144I mutation, which in human MSH6 causes inherited somatic defects in MMR resulting in increased development of hereditary non polyposis colorectal cancer , is located in the DNA binding surface of the PWWP domain. However, it only moderately affects domain stability, and it does not perturb DNA binding in vitro. |
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