title: MutSβ promotes trinucleotide repeat expansion by recruiting DNA polymerase β to nascent (CAG)n or (CTG)n hairpins for error-prone DNA synthesis.
abstract: Expansion of (CAG)•(CTG) repeats causes a number of familial neurodegenerative disorders. Although the underlying mechanism remains largely unknown, components involved in DNA mismatch repair, particularly mismatch recognition protein MutSβ (a MSH2-MSH3 heterodimer), are implicated in (CAG)•(CTG) repeat expansion. In addition to recognizing small insertion-deletion loop-outs, MutSβ also specifically binds DNA hairpin imperfect heteroduplexes formed within (CAG)n•(CTG)n 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 interacts with DNA polymerase β (Polβ) and stimulates Polβ-catalyzed (CAG)n or (CTG)n hairpin retention. Consistent with these in vitro observations, MutSβ and Polβ 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)n or (CTG)n hairpins by MutSβ and Polβ during DNA replication and/or repair: MutSβ recognizes (CAG)n or (CTG)n hairpins formed in the nascent DNA strand, and recruits Polβ 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.
authors.affiliation: Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China.|Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1450 Biggy Street, Los Angeles, CA 90033, USA.
authors.forename: Jinzhen
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1450 Biggy Street, Los Angeles, CA 90033, USA.
authors.forename: Liya
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Leffak
authors.affiliation: Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China.|Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1450 Biggy Street, Los Angeles, CA 90033, USA.
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Li
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000096:biosynthesis*; D053843:DNA Mismatch Repair; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D006367:HeLa Cells; D006801:Humans; D055029:Inverted Repeat Sequences; D018613:Microscopy, Confocal; D000074080:MutS Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D019680:Trinucleotide Repeat Expansion
chemical_list: D011994:Recombinant Proteins; D004247:DNA; D004258:DNA Polymerase III; D019951:DNA Polymerase beta; D000074080:MutS Proteins