PMID:22186889

Citation	Shukla, PC, Singh, KK, Quan, A, Al-Omran, M, Teoh, H, Lovren, F, Cao, L, Rovira, II, Pan, Y, Brezden-Masley, C, Yanagawa, B, Gupta, A, Deng, CX, Coles, JG, Leong-Poi, H, Stanford, WL, Parker, TG, Schneider, MD, Finkel, T and Verma, S (2011) BRCA1 is an essential regulator of heart function and survival following myocardial infarction. Nat Commun 2:593
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.
Links	PubMed PMC3247816 Online version:10.1038/ncomms1601
Keywords	Adaptation, Physiological; Adult; Animals; Apoptosis/genetics; BRCA1 Protein/deficiency; BRCA1 Protein/genetics; Breast Neoplasms/genetics; DNA Breaks, Double-Stranded; Female; Gene Deletion; Humans; Male; Mice; Mice, Knockout; Mutation; Myocardium/metabolism; Myocardium/pathology; Myocytes, Cardiac/cytology; Myocytes, Cardiac/metabolism; Ovarian Neoplasms/genetics; Reperfusion Injury/genetics; Reperfusion Injury/metabolism; Signal Transduction; Tumor Suppressor Protein p53/deficiency; Tumor Suppressor Protein p53/genetics; Ventricular Remodeling/genetics
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:BRCA1		GO:0006302: double-strand break repair	ECO:0000315:		P		Figure 4e. Higher levels of γH2A.X signal for double strand break repair.	complete CACAO 3907
MOUSE:BRCA1	involved_in	GO:0006302: double-strand break repair	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:BRCA1		GO:0006302: double-strand break repair	ECO:0000314:		P		Figure 6c & 6d. Higher levels of γH2A.X signal for double strand break repair.	complete CACAO 3909
HUMAN:BRCA1	involved_in	GO:0006302: double-strand break repair	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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