Identification of a BRCA1-mRNA splicing complex required for efficient DNA repair and maintenance of genomic stability.
Bottom Line: Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers.Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery.Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types.
Affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. Electronic address: email@example.com.Show MeSH
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Mentions: Given that loss of BRCA1/BCLAF1-mediated splicing of ATRIP, BACH1, and EXO1 results in reduced but not absent protein levels following DNA damage, we examined whether reduction of these proteins could contribute to the DNA damage sensitivity observed in BRCA1/BCLAF1-depleted cells. Indeed, reduction but not complete absence of any of these proteins, using titrated siRNA concentrations, resulted in sensitization to IR induced DNA damage (Figures S7A and S7B). In contrast, ectopic expression of ATRIP, BACH1, or EXO1 alone was unable to rescue the sensitivity of BRCA1- or BCLAF1-depleted cells to IR (data not shown). However, the combined ectopic expression of ATRIP, BACH1, and EXO1 was able to partially rescue the IR sensitivity of both BRCA1- and BCLAF1-depleted cells, suggesting that BRCA1/BCLAF1-mediated splicing of these genes is required, at least in part, for BRCA1 and BCLAF1’s ability to mediate resistance to DNA damaging agents (Figures 7A and S7C).
Affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. Electronic address: firstname.lastname@example.org.