The Mismatch-Binding Factor MutSβ Can Mediate ATR Activation in Response to DNA Double-Strand Breaks

0455784 - ÚMG 2016 RIV US eng J - Journal Article
Burdová, Kamila - Mihaljevic, B. - Sturzenegger, A. - Chappidi, N. - Janščák, Pavel
The Mismatch-Binding Factor MutSβ Can Mediate ATR Activation in Response to DNA Double-Strand Breaks.
Molecular Cell. Roč. 59, č. 4 (2015), s. 603-614. ISSN 1097-2765. E-ISSN 1097-4164
R&D Projects: GA ČR GAP305/10/0281; GA ČR(CZ) GA14-05743S
Grant - others:Oncosuisse(CH) KLS-02344-02-2009; Swiss National Science Foundation(CH) 31003A_146206; Novartis Foundation for Medical and Biological Research(CH) 11A16
Institutional support: RVO:68378050
Keywords : Ataxia telangiectasia-mutated and Rad3-related (ATR) protein kinase * DNA-damage response * DNA Double-Strand Breaks
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 13.958, year: 2015

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 MutS beta, 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 MutS beta 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 MutS beta 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 MutS beta.
Permanent Link: http://hdl.handle.net/11104/0256406