Functional characterisation of a novel BRCA1-mRNA splicing complex that is mutated in multiple cancers.

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Women who are born with an inherited mutation in the BRCA1 gene have a very high lifetime risk of developing breast and ovarian cancer. These women tend to have a strong family history of breast cancer and can develop breast cancer at a young age. Additionally, a large proportion of breast cancer that develop sporadically (non-inherited breast cancers) have lost the function of the BRCA1 gene. BRCA1s primary role in cells is to repair and maintain DNA and by doing this BRCA1 protects cells from being able to turn into cancers. However, the exact mechanisms through which BRCA1 protects and repairs damaged DNA remain unknown. Nevertheless, recently there have been significant advances in how BRCA1 related cancers are treated with the advent of "targeted" cancer therapies called PARP inhibitors that specifically kill cancers like BRCA1 linked cancers that have defects in their ability to repair damaged DNA. We have recently identified a new function for BRCA1 where it, with the help of other proteins called mRNA splicing proteins, helps cells to repair damaged DNA by regulating the levels of DNA repair proteins within a cell and ensuring there is enough of these proteins to repair DNA that has been damaged. Recently, a number of mutations have also been found in a significant proportion of breast, ovarian and haematological cancers in the mRNA splicing proteins that help BRCA1 carry out this new function. The proposed research in this project aims to: 1) Identify if and how hereditary mutations in BRCA1 affect this new function of BRCA1 helping us to understand whether this new function of BRCA1 really plays a role in the development of hereditary cancers. 2) Identify which DNA repair proteins that BRCA1 and the other mRNA splicing proteins, regulate are important for BRCA1 to carry out it's DNA repair functions.3) Understand how cancer associated mutations in the mRNA splicing proteins that help BRCA1 repair damaged DNA affect the way these proteins are able to help BRCA1 repair damaged DNA and how they affect the way that cancers respond to different treatments. The proposed research will add significantly to our understanding of how BRCA1 works to prevent the development of cancer. Additionally, this research may lead to the development of new tests to help decide which treatments specific cancer patients will benefit from and may also identify new proteins associated with cancer that could be targeted for future therapies.