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Investigating the role of 53BP1, a key regulator of double strand break repair

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  • Full or part time
    Dr Watts
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Failure to maintain genetic stability can result in inherited genetic disorders, cancer or cell death. Thus, understanding how cells respond to DNA damage and identification of processes involved in the DNA damage response has important implications for human health. Additionally, information gained about such processes is beginning to be exploited to identify targeted anti-cancer therapies. As part of such investigations, we are characterising the roles of the p53 tumour suppressor binding protein, 53BP1. This protein has a key function in determining how DNA double strand breaks (DSBs) are repaired: it promotes non-homologous end-joining (NHEJ) and inhibits homologous recombination. It has a number of domains that are involved in protein-protein interactions, which are required for specific aspects of DNA repair and DNA integrity checkpoint maintenance. As part of our analysis, we have demonstrated that, like its S. pombe orthologue Crb2, the 53BP1 BRCT (BRCA1 C-terminal) domains interact with the DNA damage marker gamma-H2AX (Kilkenny et al 2008; Baldock et al 2015), and that this interaction is required for repair of DSBs in G1. We showed that this involves the tethering of the DNA integrity checkpoint kinase ATM. The aim of this PhD project is to further define the role of 53BP1 – specifically to (a) characterise its role in G1 and the nature of its interactions with other proteins, and (b) to investigate its role repair pathway choice in G2 and in particular its relationship with BRCA1.

Funding Notes

This research opportunity is for self funded students only

References

Relevant references
Densham, R.M., Garvin, A.J., Stone, H.R., Strachan, J., Baldock, R.A. Daza-Martin, M., Fletcher, A., Blair-Reed, S., Beesley, J., Johal, B., Pearl, L.H., Neely, R., Keep, N.H., Watts, F.Z and Morris, J.R. 2016, Human BRCA1-BARD1 ubiquitin ligase activity counters chromatin barriers to DNA resection. Nature Str. Mol. Biol. May 30th.

Baldock, R.A., Day, M., Wilkinson, O.J., Cloney, R., Jeggo, P.A., Oliver, A.W., Watts, F.Z. & Pearl, L.H., 2015, ATM Localization and Heterochromatin Repair Depend on Direct Interaction of the 53BP1-BRCT2 Domain with γH2AX, Cell reports 13(10) 2081-2089.

Watts, F.Z. & Brissett, N.C., 2010, Linking up and interacting with BRCT domains, DNA Repair, 9(2), pp. 103-8.

Kilkenny, M.L., Dore, A.S., Roe, S.M., Nestoras, K., Ho, J.C., Watts, F.Z. & Pearl, L.H., 2008, Structural and functional analysis of the Crb2-BRCT2 domain reveals distinct roles in checkpoint signaling and DNA damage repair, Genes Dev, 22(15), pp. 2034-47.

How good is research at University of Sussex in Biological Sciences?

FTE Category A staff submitted: 47.61

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