title: BRCA1 is an essential regulator of heart function and survival following myocardial infarction.
abstract: The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated pro-apoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure.
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, St Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
authors.forename: Praphulla C
authors.initials: PC
authors.lastname: Shukla
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.forename: Hwee
authors.initials: H
authors.lastname: Teoh
authors.forename: Fina
authors.initials: F
authors.lastname: Lovren
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.forename: Ilsa I
authors.initials: II
authors.lastname: Rovira
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Christine
authors.initials: C
authors.lastname: Brezden-Masley
authors.forename: Bobby
authors.initials: B
authors.lastname: Yanagawa
authors.forename: Aanika
authors.initials: A
authors.lastname: Gupta
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: John G
authors.initials: JG
authors.lastname: Coles
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Parker
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D000222:Adaptation, Physiological; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D016159:Tumor Suppressor Protein p53