2. Academic Validation
  3. RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis

RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis

  • Mol Cell. 2017 Jun 1;66(5):658-671.e8. doi: 10.1016/j.molcel.2017.05.006.
Stefano Di Marco 1,  Zdenka Hasanova 2,  Radhakrishnan Kanagaraj 1,  Nagaraja Chappidi 1,  Veronika Altmannova 3,  Shruti Menon 1,  Hana Sedlackova 2,  Jana Langhoff 1,  Kalpana Surendranath 4,  Daniela Hühn 1,  Rahul Bhowmick 5,  Victoria Marini 2,  Stefano Ferrari 1,  Ian D Hickson 5,  Lumir Krejci 6,  Pavel Janscak 7
Affiliations

Affiliations

  • 1 Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • 2 Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A7, Brno 62500, Czech Republic.
  • 3 Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A7, Brno 62500, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Pekarska 53, Brno 656 91, Czech Republic.
  • 4 Department of Biomedical Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK.
  • 5 Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Insitute Building 18.1, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
  • 6 Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A7, Brno 62500, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Pekarska 53, Brno 656 91, Czech Republic; National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5/A4, 625 00, Brno, Czech Republic. Electronic address: lkrejci@chemi.muni.cz.
  • 7 Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: pjanscak@imcr.uzh.ch.
PMID: 28575661 DOI: 10.1016/j.molcel.2017.05.006
Abstract

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 3'-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.

Keywords

MUS81; RAD51 filament; RECQ5; common fragile sites; genomic instability; mitotic DNA synthesis; replication stress.

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