title: Rad54 and Mus81 cooperation promotes DNA damage repair and restrains chromosome missegregation.
abstract: Rad54 and Mus81 mammalian proteins physically interact and are important for the homologous recombination DNA repair pathway; however, their functional interactions in vivo are poorly defined. Here, we show that combinatorial loss of Rad54 and Mus81 results in hypersensitivity to DNA-damaging agents, defects on both the homologous recombination and non-homologous DNA end joining repair pathways and reduced fertility. We also observed that while Mus81 deficiency diminished the cleavage of common fragile sites, very strikingly, Rad54 loss impaired this cleavage to even a greater extent. The inefficient repair of DNA double-strand breaks (DSBs) in Rad54(-/-)Mus81(-/-) cells was accompanied by elevated levels of chromosome missegregation and cell death. Perhaps as a consequence, tumor incidence in Rad54(-/-)Mus81(-/-) mice remained comparable to that in Mus81(-/-) mice. Our study highlights the importance of the cooperation between Rad54 and Mus81 for mediating DNA DSB repair and restraining chromosome missegregation.
authors.affiliation: Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: S El
authors.initials: SE
authors.lastname: Ghamrasni
authors.affiliation: Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Cardoso
authors.affiliation: Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: K K N
authors.initials: KK
authors.lastname: Guturi
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Ageing, University of Copenhagen, Panum Institute, Copenhagen, Denmark.
authors.forename: V A
authors.initials: VA
authors.lastname: Bjerregaard
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Ageing, University of Copenhagen, Panum Institute, Copenhagen, Denmark.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine and Tembusu College, National University of Singapore, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Venkatesan
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine and Tembusu College, National University of Singapore, Singapore.
authors.forename: M P
authors.initials: MP
authors.lastname: Hande
authors.affiliation: Department of Pharmaceutical Sciences, Division of Biomolecular Science, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J T
authors.initials: JT
authors.lastname: Henderson
authors.affiliation: Department of pathology, University of Ontario Institute of Technology, Oshawa, Ontario, Canada.
authors.forename: O
authors.initials: O
authors.lastname: Sanchez
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Ageing, University of Copenhagen, Panum Institute, Copenhagen, Denmark.
authors.forename: I D
authors.initials: ID
authors.lastname: Hickson
authors.affiliation: Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Hakem
authors.affiliation: Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Hakem
mesh_terms: D000818:Animals; D002875:Chromosomes / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D059766:DNA End-Joining Repair / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D004720:Endonucleases; C498773:Mus81 protein, mouse; D004265:DNA Helicases; C103534:Rad54l protein, mouse