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.

• MeSH
• aktivace enzymů MeSH
• ATM protein metabolismus   MeSH
• DNA vazebné proteiny chemie   metabolismus   fyziologie   MeSH
• dvouřetězcové zlomy DNA * MeSH
• fosforylace MeSH
• HEK293 buňky MeSH
• homolog 2 proteinu MutS chemie   fyziologie   MeSH
• homolog 3 proteinu MutS MeSH
• homologní rekombinace MeSH
• jednovláknová DNA chemie   MeSH
• lidé MeSH
• oprava DNA MeSH
• posttranslační úpravy proteinů MeSH
• transport proteinů MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATM protein MeSH
• ATR protein, human MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• G-T mismatch-binding protein MeSH Prohlížeč
• homolog 2 proteinu MutS MeSH
• homolog 3 proteinu MutS MeSH
• jednovláknová DNA MeSH
• MSH2 protein, human MeSH Prohlížeč
• MSH3 protein, human MeSH Prohlížeč