title: Cooperation of Blm and Mus81 in development, fertility, genomic integrity and cancer suppression.
abstract: BLM is a DNA helicase important for the restart of stalled replication forks and for homologous recombination (HR) repair. Mutations of BLM lead to Bloom Syndrome, a rare autosomal recessive disorder characterized by elevated levels of sister chromatid exchanges (SCEs), dwarfism, immunodeficiency, infertility and increased cancer predisposition. BLM physically interacts with MUS81, an endonuclease involved in the restart of stalled replication forks and HR repair. Herein we report that loss of Mus81 in Blm hypomorph mutant mice leads to infertility, and growth and developmental defects that are not observed in single mutants. Double mutant cells and mice were hypersensitive to Mitomycin C and γ-irradiation (IR) compared with controls and their repair of DNA double-strand breaks (DSBs) mediated by HR pathway was significantly defective, whereas their non-homologous-end-joining repair was elevated compared with controls. We also demonstrate the importance of the loss of the nuclease activity of Mus81 in the defects observed in Mus81(-/-) and double mutant cells. Exacerbated IR-induced chromosomal aberration was observed in double mutant mice and despite their reduced SCE levels, these mutants showed increased tumorigenesis risks. Our data highlight the importance of Mus81 and Blm in DNA DSB repair pathways, fertility, development and cancer.
authors.affiliation: 1] Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada [2] Laboratory of Biotechnology, Faculty of Sciences DHEM, University SMBA, Fez, Morocco.
authors.forename: S
authors.initials: S
authors.lastname: El Ghamrasni
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Cardoso
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Halaby
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine and Tembusu College, National University of Singapore, Singapore, Singapore.
authors.forename: D
authors.initials: D
authors.lastname: Zeegers
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Harding
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Kumareswaran
authors.affiliation: Department of Obstetrics and Gynecology and Physiology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Yavorska
authors.affiliation: Laboratory of Biotechnology, Faculty of Sciences DHEM, University SMBA, Fez, Morocco.
authors.forename: N
authors.initials: N
authors.lastname: Chami
authors.affiliation: Department of Obstetrics and Gynecology and Physiology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Jurisicova
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 Physiology, Yong Loo Lin School of Medicine and Tembusu College, National University of Singapore, Singapore, Singapore.
authors.forename: M P
authors.initials: MP
authors.lastname: Hande
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Bristow
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Hakem
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Hakem
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000528:radiation effects; D002869:Chromosome Aberrations / Q000139:chemically induced / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D059766:DNA End-Joining Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005720:Gamma Rays / Q000009:adverse effects; D008223:Lymphoma / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016685:Mitomycin / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D053484:RecQ Helicases / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016685:Mitomycin; D004720:Endonucleases; C498773:Mus81 protein, mouse; C097151:Bloom syndrome protein; D053484:RecQ Helicases