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
AUTHORS (20)
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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