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

Praphulla C. Shukla, Krishna K. Singh, Adrian Quan, Mohammed Al-Omran, Hwee Teoh, Fina Lovren, Liu Cao, Ilsa I. Rovira, Yi Pan, Christine Brezden-Masley, Bobby Yanagawa, Aanika Gupta, Chu-Xia Deng, John G. Coles, Howard Leong-Poi, William L. Stanford, Thomas G. Parker, Michael D. Schneider, Toren Finkel and Subodh Verma ()
Additional contact information
Praphulla C. Shukla: St Michael's Hospital
Krishna K. Singh: St Michael's Hospital
Adrian Quan: St Michael's Hospital
Mohammed Al-Omran: Keenan Research Centre in the Li Ka Shing Knowledge Institute at St Michael's Hospital
Hwee Teoh: St Michael's Hospital
Fina Lovren: St Michael's Hospital
Liu Cao: Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University
Ilsa I. Rovira: Center for Molecular Medicine, National Heart Lung and Blood Institute
Yi Pan: St Michael's Hospital
Christine Brezden-Masley: Keenan Research Centre in the Li Ka Shing Knowledge Institute at St Michael's Hospital
Bobby Yanagawa: St Michael's Hospital
Aanika Gupta: McMaster University
Chu-Xia Deng: Mammalian Genetics Section, Genetics of Development and Disease Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
John G. Coles: University of Toronto
Howard Leong-Poi: Keenan Research Centre in the Li Ka Shing Knowledge Institute at St Michael's Hospital
William L. Stanford: Sprott Centre for Stem Cell Research, University of Ottawa
Thomas G. Parker: Keenan Research Centre in the Li Ka Shing Knowledge Institute at St Michael's Hospital
Michael D. Schneider: British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London
Toren Finkel: Center for Molecular Medicine, National Heart Lung and Blood Institute
Subodh Verma: St Michael's Hospital

Nature Communications, 2011, vol. 2, issue 1, 1-11

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1601

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