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标题：Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair
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作者：Jochen Genschel ; Lyudmila Y. Kadyrova ; Ravi R. Iyer 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：19
页码：4930-4935
DOI：10.1073/pnas.1702561114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Eukaryotic MutLα (mammalian MLH1–PMS2 heterodimer; MLH1–PMS1 in yeast) functions in early steps of mismatch repair as a latent endonuclease that requires a mismatch, MutSα/β, and DNA-loaded proliferating cell nuclear antigen (PCNA) for activation. We show here that human PCNA and MutLα interact specifically but weakly in solution to form a complex of approximately 1:1 stoichiometry that depends on PCNA interaction with the C-terminal endonuclease domain of the MutLα PMS2 subunit. Amino acid substitution mutations within a PMS2 C-terminal ⁷²¹QRLIAP motif attenuate or abolish human MutLα interaction with PCNA, as well as PCNA-dependent activation of MutLα endonuclease, PCNA- and DNA-dependent activation of MutLα ATPase, and MutLα function in in vitro mismatch repair. Amino acid substitution mutations within the corresponding yeast PMS1 motif (⁷²³QKLIIP) reduce or abolish mismatch repair in vivo. Coupling of a weak allele within this motif (⁷²³AKLIIP) with an exo1 Δ null mutation, which individually confer only weak mutator phenotypes, inactivates mismatch repair in the yeast cell.
关键词：DNA repair ; mismatch repair ; MutLalpha ; proliferating cell nuclear antigen ; endonuclease