MutSβ promotes trinucleotide repeat expansion by recruiting DNA polymerase β to nascent （CAG）n or （CTG）n hairpins for error-prone DNA synthesis  

作　　者：Jinzhen Guo Liya Gu Michael Leffak Guo-Min Li 

机构地区：[1]Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China [2]Department of Bio- chemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1450 Biggy Street, Los Angeles, CA 90033, USA [3]Department of Biochemistry and Molecular Biology, Boonshofl School of Medicine, Wright State University, Dayton, OH 45435, USA

出　　处：《Cell Research》2016年第7期775-786,共12页细胞研究（英文版）

摘　　要：Expansion of （CAG）.（CTG） repeats causes a number of familial neurodegenerative disorders. Although the un- derlying mechanism remains largely unknown, components involved in DNA mismatch repair, particularly mis- match recognition protein MutSβ （a MSH2-MSH3 heterodimer）, are implicated in （CAG）o（CTG） repeat expansion. In addition to recognizing small insertion-deletion loop-outs, MutSβalso specifically binds DNA hairpin imperfect heteroduplexes formed within （CAG）a-（CTG）, sequences. However, whether or not and how MutSβ binding triggers expansion of （CAG）.（CTG） repeats remain unknown. We show here that purified recombinant MutSβ physically in- teracts with DNA polymeraseβ （Polβ） and stimulates Polβ-catalyzed （CAG）n or （CTG）, hairpin retention. Consistent with these in vitro observations, MutSβ and Poll; interact with each other in vivo, and colocalize at （CAG）.（CTG） repeats during DNA replication. Our data support a model for error-prone processing of （CAG）, or （CTG）, hairpins by MutSβ and Polβ during DNA replication and/or repair： MutS[i recognizes （CAG）. or （CTG）= hairpins formed in the nascent DNA strand, and recruits Polp to the complex, which then utilizes the hairpin as a primer for extension, leading to （CAG）.（CTG） repeat expansion. This study provides a novel mechanism for trinucleotide repeat expansion in both dividing and non-dividing cells.

关 键 词：trinucleotide repeat expansion MutSβ DNA polymerase β （CAG）..（CTG）. hairpin 

分 类 号：Q343[生物学—遗传学] Q78