TY - JOUR
T1 - BRCA1 is an essential regulator of heart function and survival following myocardial infarction
AU - Shukla, Praphulla C.
AU - Singh, Krishna K.
AU - Quan, Adrian
AU - Al-Omran, Mohammed
AU - Teoh, Hwee
AU - Lovren, Fina
AU - Cao, Liu
AU - Rovira, Ilsa I.
AU - Pan, Yi
AU - Brezden-Masley, Christine
AU - Yanagawa, Bobby
AU - Gupta, Aanika
AU - Deng, Chu Xia
AU - Coles, John G.
AU - Leong-Poi, Howard
AU - Stanford, William L.
AU - Parker, Thomas G.
AU - Schneider, Michael D.
AU - Finkel, Toren
AU - Verma, Subodh
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84455180756&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84455180756&partnerID=8YFLogxK
U2 - 10.1038/ncomms1601
DO - 10.1038/ncomms1601
M3 - Article
C2 - 22186889
AN - SCOPUS:84455180756
SN - 2041-1723
VL - 2
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 593
ER -