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Title: Functional analysis of the BRCA1 protein through mutation & complex formation identifies a novel BRCA1 interacting protein
Author: Burn, Philip
ISNI:       0000 0004 6061 9606
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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Mutations in the BRCA1 tumour suppressor gene are associated with significantly elevated risks of develop breast or ovarian carcinomas, up to 80% or 40% respectively by age 70. The anti-tumourigenic activity of the wild-type protein product is the result of participation in a number of distinct but overlapping protective pathways; DNA damage repair, transcription & splicing, cell cycle regulation, ubiquitination & regulation of apoptosis. Through modulating these cellular mechanisms, BRCA1 is able to participate in the preservation of genomic integrity. Consequently, cells lacking functional BRCA1 exhibit traits associated with genetic instability; gross chromosomal translocations, often involving multiple, non-homologous chromosomes; as well as deletions and/or amplifications of genetic material. Furthermore, BRCA1 deficient cells lack fully functional DNA repair processes and are sensitive to genotoxic agents. It has been demonstrated that BRCA1 acts principally as a scaffold protein, and mediates the formation of a number of complexes in the cell with unique functions. The BRCA1-associated factors in these complexes participate in the pathways described above, and ultimately contribute to BRCA1-mediated tumour suppression. Accordingly, it is reasonable to suggest that a significant proportion of BRCA1 function is a product of the factors with which it interacts. Protein interaction sites have been described across the entire length of the BRCA1 protein sequence, and some specific regions have been broadly associated with particular functions or pathways, for instance the C-terminus is associated with DNA damage response, whilst the N-terminus is required for ubiquitination. However, there is limited information as yet associating specific domains of the BRCA1 protein with preventing tumour formation or disease progression. In this study, we have attempted to assess the contribution of specific domains to BRCA1 function and tumour suppression through directly analysing the effect of pathogenic mutations on BRCA1 function and how phosphorylation of BRCA1 contributes to complex formation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Not available Qualification Level: Doctoral
EThOS ID:  DOI: Not available