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Title: Transcriptional role of BRCA1 in the DNA damage response
Author: Barros, Eliana Margarida Soares da Costa Henriques de
ISNI:       0000 0004 5917 5673
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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BRCA1 plays a key role in several cellular pathways, including DNA damage response, transcriptional regulation and DNA double strand break repair. However, BRCA1 mutation carriers primarily develop breast and ovarian cancers, both of which are estrogen-regulated tissues. Estrogen exposure is a well-known breast cancer risk factor and is postulated to promote tumorigenesis directly through activation of ERα, and indirectly by the conversion of estrogen to genotoxic metabolites. However, the majority of BRCA1 mutated tumours are ER-negative. Experiments, in our laboratory have demonstrated that estrogen and estrogen metabolites induce DNA double strand breaks in a BRCA1 dependent manner and that functional BRCA1 is required for the repair of those breaks. Additionally, we have demonstrated that BRCA 1 regulates estrogen metabolism through transcriptional regulation of estrogen metabolising enzymes CYP1A1, CYP3A4 and NQ01. Overall, we present a model of estrogen mediated breast cancer in BRCA 1 carriers, where the absence of BRCA 1 causes the deregulation of estrogen metabolism, resulting in increased DNA DSBs and loss of efficient DNA repair, thereby increasing genomic instability and contributing to cancer development. BRCA1 germline mutations play a determinant role in the development of breast and ovarian tumours, as illustrated by our results, nevertheless BRCA 1's accurate functions are critical to all cells, particularly in maintaining genomic stability through its function in the DNA damage response. Recently, our group has identified a novel DNA damage induced complex, consisting of BRCA 1, BCLAF1 and other components of the mRNA splicing machinery. This complex regulates the pre-mRNA splicing of a large subgroup of genes, mainly involved in DNA damage signalling and repair. Disruption of the complex results in sensitivity to DNA damage and defective DNA repair, thereby promoting genomic instability that may ultimately contribute to cancer development. Phosphorylation of BRCA 1 is required for the assembly of this complex, however the functional importance of BCLAF1 in this complex was unknown. Furthermore, cancer associated mutations have been found in several genes of this complex, including BCLAF1, suggesting these may have a role in carcinogenesis. Our results showed that BCLAF1, like BRCA 1, is phosphorylated in response to DNA damage and that this modification may influence its function within the BRCA1/BCLAF1 splicing complex. In particular, phosphorylation at Ser122 and Ser161 seem to be, at least partially, required for effective DNA damage repair. Furthermore, a similar functional defect was observed with the cancer associated mutation D451 E within BCLAF1, suggesting that the defective DNA repair may be capable of driving genomic instability and/or tumourigenesis. Additionally, our data supports a role for BCLAF1 in autophagy and apoptosis, suggesting there is interplay between these pathways that culminates in cell death after BCLAF1 overexpression, independently of DNA damage. In summary, our data demonstrates that BCLAF1 is a multi-functional protein involved in distinct pathways, such as autophagy, apoptosis and mRNA splicing, which can be triggered by different protein expression levels, post-translational modifications or external stimuli. BCLAF1's role in carcinogenesis requires further investigation, but our study highlights the importance of this protein in a new mRNA splicing complex, required for maintaining genomic stability. In conclusion, our results highlight that the presence of functional BRCA 1 is critical to all cells, in order to maintain genomic stability and suppress tumour development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available