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 language | English (US) |
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Pages (from-to) | 775-786 |
Number of pages | 12 |
Journal | Cell Research |
Volume | 26 |
Issue number | 7 |
DOIs | |
State | Published - Jul 1 2016 |
Keywords
- (CAG)•(CTG) hairpin
- DNA polymerase β
- MutSβ
- trinucleotide repeat expansion
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology