Abstract
The precise manner in which physical changes to the breast cancer susceptibility protein (BRCA1) affect its role in DNA repair events remain unclear. Indeed, cancer cells harboring mutations in BRCA1 suffer from genomic instability and increased DNA lesions. Here, we used a combination of molecular imaging and biochemical tools to study the properties of the BRCA1 in human cancer cells. Our results reveal new information for the manner in which full-length BRCA1 engages its binding partner, the BRCA1-associated Ring Domain protein (BARD1) under oxidative stress conditions. We also show how physical differences between wild type and mutated BRCA15382insC impact the cell’s response to oxidative damage. Overall, we demonstrate how clinically relevant changes to BRCA1 affect its structure-function relationship in hereditary breast cancer.
Highlights
Germline mutations in the breast cancer susceptibility gene (BRCA1) are heavily linked to familial breast and ovarian cancers[1,2,3,4]
How does oxidative stress effect wild type BRCA1 in breast cancer cells? To investigate the manner in which BRCA1 responds to oxidative stress in breast cancer cells, we employed a combination of molecular imaging and biochemical tools
Experiments performed on control cells showed approximately the same level of interaction as the stressed cells. These results indicated that wild type BRCA1 was relatively stable under oxidative conditions in the nucleus, and that its association with BARD1 was strongly maintained
Summary
Germline mutations in the breast cancer susceptibility gene (BRCA1) are heavily linked to familial breast and ovarian cancers[1,2,3,4]. Critical windows of vulnerability correlate with the early onset of breast cancer[7] These events coincide with a buildup of DNA lesions in mammary tissue as reactive oxygen species are formed from the metabolic processing of estrogen[8]. The BRCA1-BARD1 heterodimer performs these operations by interacting with other repair proteins, such as BRCA2, at damaged sites on DNA. In this context, BRCA1 acts as a tumor suppressor to ensure fidelity in the genome[11,12]. Our results reveal how modifications to BRCA1 influence nuclear events that can weaken DNA repair response
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