Journal
MOLECULAR CELL
Volume 66, Issue 5, Pages 658-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2017.05.006
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Funding
- Swiss National Science Foundation [31003A_146206, 31003A_166451]
- Promedica Foundation [GHDE AUGK-DZZ 1226/M]
- Stiftung zur Krebsbekampfung
- Czech Science Foundation [13-26629S, 17-17720S]
- European Regional Development Fund - Project FNUSA- ICRC [CZ.1.05/1.1.00/02.0123]
- Research Support Programme (GAMU) [MUNI/M/1894/2014]
- University of Westminster's Faculty of Science and Technology
- Danish National Research Foundation [DNRF115]
- Nordea Foundation
- European Research Council [321717]
- UBS AG
- Danish Medical Research Council
- Swiss National Science Foundation (SNF) [31003A_166451, 31003A_146206] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [321717] Funding Source: European Research Council (ERC)
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The MUS81-EME1 endonuclease cleaves late replication intermediates at common fragile sites (CFSs) during early mitosis to trigger DNA-repair synthesis that ensures faithful chromosome segregation. Here, we show that these DNA transactions are promoted by RECQ5 DNA helicase in a manner dependent on its Ser727 phosphorylation by CDK1. Upon replication stress, RECQ5 associates with CFSs in early mitosis through its physical interaction with MUS81 and promotes MUS81-dependent mitotic DNA synthesis. RECQ5 depletion or mutational inactivation of its ATP-binding site, RAD51-interacting domain, or phosphorylation site causes excessive binding of RAD51 to CFS loci and impairs CFS expression. This leads to defective chromosome segregation and accumulation of CFS-associated DNA damage in G1 cells. Biochemically, RECQ5 alleviates the inhibitory effect of RAD51 on 30-flap DNA cleavage by MUS81-EME1 through its RAD51 filament disruption activity. These data suggest that RECQ5 removes RAD51 filaments stabilizing stalled replication forks at CFSs and hence facilitates CFS cleavage by MUS81-EME1.
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