The Mismatch-Binding Factor MutSβ Can Mediate ATR Activation in Response to DNA Double-Strand Breaks
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26212458
DOI
10.1016/j.molcel.2015.06.026
PII: S1097-2765(15)00498-0
Knihovny.cz E-resources
- MeSH
- Enzyme Activation MeSH
- Ataxia Telangiectasia Mutated Proteins metabolism MeSH
- DNA-Binding Proteins chemistry metabolism physiology MeSH
- DNA Breaks, Double-Stranded * MeSH
- Phosphorylation MeSH
- HEK293 Cells MeSH
- MutS Homolog 2 Protein chemistry physiology MeSH
- MutS Homolog 3 Protein MeSH
- Homologous Recombination MeSH
- DNA, Single-Stranded chemistry MeSH
- Humans MeSH
- DNA Repair MeSH
- Protein Processing, Post-Translational MeSH
- Protein Transport MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Ataxia Telangiectasia Mutated Proteins MeSH
- ATR protein, human MeSH Browser
- DNA-Binding Proteins MeSH
- G-T mismatch-binding protein MeSH Browser
- MutS Homolog 2 Protein MeSH
- MutS Homolog 3 Protein MeSH
- DNA, Single-Stranded MeSH
- MSH2 protein, human MeSH Browser
- MSH3 protein, human MeSH Browser
Ataxia telangiectasia-mutated and Rad3-related (ATR) protein kinase, a master regulator of DNA-damage response, is activated by RPA-coated single-stranded DNA (ssDNA) generated at stalled replication forks or DNA double-strand breaks (DSBs). Here, we identify the mismatch-binding protein MutSβ, a heterodimer of MSH2 and MSH3, as a key player in this process. MSH2 and MSH3 form a complex with ATR and its regulatory partner ATRIP, and their depletion compromises the formation of ATRIP foci and phosphorylation of ATR substrates in cells responding to replication-associated DSBs. Purified MutSβ binds to hairpin loop structures that persist in RPA-ssDNA complexes and promotes ATRIP recruitment. Mutations in the mismatch-binding domain of MSH3 abolish the binding of MutSβ to DNA hairpin loops and its ability to promote ATR activation by ssDNA. These results suggest that hairpin loops might form in ssDNA generated at sites of DNA damage and trigger ATR activation in a process mediated by MutSβ.
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