Understanding the BRCA1 N-terminus
The highest density of amino acid changes in cancer patients are found in the N-terminal portion for BRCA1. While some, largely zinc-ligating residues are known to be pathogenic, others are of unknown clinical significance.
This project aims to map the sensitivity of the N-terminus to known interacting proteins as a means to identifying molecular pathways relevant to BRCA1 dysfunction.
As part of this interest we are part of the AFFECT consortia. Which aims to gather information on the tumours from carriers of BRCA1 missense carriers in order to increase the ability to ‘call’ the likelihood that currently unclassified variants are or are not pathogenic.
We are using gene editing to generate cell lines bearing some of these changes within the endogenous locus in complement with our animal model of breast cancer development.
Activity of conserved regions of BRCA1
Small patches of high levels of conservation occur beyond the N- and C-termini of BRCA1. This project aims to establish whether these, and the patient variants found within them, have any functional role. And if so what that might be.
Regulation of BRCA1
Inactivation of BRCA1, such as promoter methylation is a potential ‘second hit’ in cancer development. In this project other means of BRCA1 regulation are explored to establish whether loss of the supporting mechanisms of BRCA1 expression relate to breast cancer development.
Ubiquitin conjugation in DNA repair
Ubiquitin conjugation plays a significant role in the co-ordination of the DNA repair response. Defects in this pathway are associated with immune-deficiency syndromes and cancer. We aim to identify new plays in the ubiquitin conjugation and de-conjugation pathways that may shed new light on this important post-translational modification.
In work in this area we have shown that the proteasomal De-ubiquitinating enzyme, POH1, is key in restricting the presence of Ubiquitin conjugates generated at sites of Double-strand breaks and restricts 53BP1 accumulation regulating DNA repair by non homologous end-joining.SUMO conjugation in DNA repair.
We have recently found that SUMO plays an important part of the BRCA1-pathway in the DNA damage response. In this project we aim to define the role of poly-SUMOlyation in DNA repair, in cancer and in development.
Other pathways of post-translational modifications are also under investigation.