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BRCA1 gene may have several roles in DNA repair

Researchers at the University of Birmingham (UoB, UK) have suggested that the gene BRCA1 may have a role in DNA repair. Furthermore, they suggest that the gene may have several distinct roles in DNA repair, indicating new avenues for future treatments against breast cancer.

Previous research has demonstrated that mutations in BRCA1 are associated with a higher risk of breast and ovarian cancer, although the exact role of the gene remains unclear. In this new study, published in Nature Structural and Molecular Biology, the researchers suggest that BRCA1 produces a protein that promotes attachment to ubiquitin and plays a vital role in DNA repair.

Ubiquitin is a protein that regulates cell processes. The researchers suggest that binding of the BRCA1 protein and ubiquitin activates ‘ubiquitin ligase activity’, which is required for homologous recombination. Previous research has demonstrated that faulty homologous recombination can lead to cancer-causing mutations. The UoB team observed that cells lacking BRCA1 ubiquitin ligase activity are sensitive to certain DNA-damaging agents that normally require homologous recombination for repair.

Jo Morris (UoB), lead author of the study, explained: “We know that loss of BRCA1 is associated with a high risk of breast cancer, so getting to grips with understanding this gene has been a major aim of breast cancer research. This study may explain why some cancer predisposing mutations are found in the front part of the BRCA1 gene – the part that allows it to function as a ubiquitin ligase.”

Following further research into how the BRCA1 protein attaches to ubiquitin, the team demonstrated that it relies on BARD1, a co-binding protein. When BARD1 was present in a mutated form, they were able to deduce the attachment function of BRCA1, observing that the BRCA1protein is required for both response to, and repair of, DNA damage.

Morris added: “Our finding that BRCA1 has several independent functions in DNA repair has implications for treatment. Clinicians are currently worried that breast cancer patients with low or absent BRCA1 may become resistant to therapeutic agents such as Olaparib. Our data show that cancer cells without BRCA1 have more than one “Achilles heel”, and so there are more ways to target cancers and therefore to prevent tumours becoming resistant to treatment.”

Sources: Densham RM, Garvin AJ, Stone HR et al. Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat. Struct. Mol. Biol. doi: 10.1038/nsmb.3236 (2016) (Epub ahead of print); www.birmingham.ac.uk/news/latest/2016/05/research-explains-the-role-of-the-gene-BRCA1-in-DNA-repair.aspx