title: Fanconi anemia signaling and Mus81 cooperate to safeguard development and crosslink repair.
abstract: Individuals with Fanconi anemia (FA) are susceptible to bone marrow failure, congenital abnormalities, cancer predisposition and exhibit defective DNA crosslink repair. The relationship of this repair defect to disease traits remains unclear, given that crosslink sensitivity is recapitulated in FA mouse models without most of the other disease-related features. Mice deficient in Mus81 are also defective in crosslink repair, yet MUS81 mutations have not been linked to FA. Using mice deficient in both Mus81 and the FA pathway protein FancC, we show both proteins cooperate in parallel pathways, as concomitant loss of FancC and Mus81 triggered cell-type-specific proliferation arrest, apoptosis and DNA damage accumulation in utero. Mice deficient in both FancC and Mus81 that survived to birth exhibited growth defects and an increased incidence of congenital abnormalities. This cooperativity of FancC and Mus81 in developmental outcome was also mirrored in response to crosslink damage and chromosomal integrity. Thus, our findings reveal that both pathways safeguard against DNA damage from exceeding a critical threshold that triggers proliferation arrest and apoptosis, leading to compromised in utero development.
authors: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.
authors: Meghan
authors: M
authors: Larin
authors: Department of Biochemistry, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S 3E1, Canada.
authors: David
authors: D
authors: Gallo
authors: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.
authors: Laura
authors: L
authors: Tamblyn
authors: Department of Biochemistry, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S 3E1, Canada.
authors: Jay
authors: J
authors: Yang
authors: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.
authors: Hudson
authors: H
authors: Liao
authors: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.
authors: Nestor
authors: N
authors: Sabat
authors: Department of Biochemistry, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S 3E1, Canada.
authors: Grant W
authors: GW
authors: Brown
authors: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada peter.mcpherson@utoronto.ca.
authors: J Peter
authors: JP
authors: McPherson
mesh_terms: D000818:Animals; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004720:Endonucleases / Q000235:genetics / Q000502:physiology*; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics / Q000502:physiology*; D016678:Genome; D051379:Mice; D018345:Mice, Knockout; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D004720:Endonucleases; C498773:Mus81 protein, mouse