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

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 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
DOI: 10.1038/ncomms1601 Publication Date: 2011-12-20T12:05:41Z
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.
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