BRCA1 is an essential regulator of heart function and survival following myocardial infarction

• DOI: 10.1038/ncomms1601
• Publication Date: 2011-12-20T12:05:41Z
• Authors: Praphulla C. Shukla; Krishna K. Singh; Adrian Quan; Mohammed Al-Omran; Hwee Teoh; Fina Lovren; Liu Cao; Ilsa I. Rovira; Yi Pan; Christine Brezden...; Bobby Yanagawa; Aanika Gupta; Chu-Xia Deng; John G. Coles; Howard Leong-Poi; William L. Stanford; Thomas G. Parker; Michael D. Schneider; Toren Finkel; Subodh Verma
• Keywords: EXPRESSION; Adult; Male; 0301 basic medicine; Physiological; Knockout; 610; DNA-DAMAGE RESPONSE; Apoptosis; Breast Neoplasms; SUSCEPTIBILITY; BREAST; Article; ACTIVATION; Double-Stranded; Mice; 03 medical and health sciences; Animals; Humans; GENE BRCA1; DNA Breaks, Double-Stranded; Myocytes, Cardiac; Adaptation; EARLY EMBRYONIC LETHALITY; Mice, Knockout; Ovarian Neoplasms; Myocytes; P53; 0303 health sciences; Science & Technology; Ventricular Remodeling; BRCA1 Protein; Myocardium; DNA Breaks; Adaptation, Physiological; APOPTOSIS; 3. Good health; Multidisciplinary Sciences; CELL-DEATH; Reperfusion Injury; Mutation; Science & Technology - Other Topics; Female; Tumor Suppressor Protein p53; Cardiac; Gene Deletion; Signal Transduction

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.