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

Jinzhen Guo, Liya Gu, Michael Leffak, Guo Min Li

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)775-786
Number of pages12
JournalCell Research
Volume26
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

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Keywords

  • (CAG)•(CTG) hairpin
  • DNA polymerase β
  • MutSβ
  • trinucleotide repeat expansion

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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