Phosphorylated Ubiquitin in the DNA damage response

Farrell, Abigail ORCID: 0000-0003-3717-1703 (2023). Phosphorylated Ubiquitin in the DNA damage response. University of Birmingham. Ph.D.

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Abstract

Ubiquitylation and phosphorylation are key post-translational modifications in the response to, and repair of, DNA double strand breaks. Signalling through these modifications is detected rapidly upon induction of damage, and continues throughout DNA repair. Phospho-proteomic studies have found that ubiquitin itself can be phosphorylated at 11 different sites. Characterisation of several of these sites has revealed that phospho-ubiquitin can give rise to specific signalling, with roles in human health and disease.
In this thesis, I show detection of a previously uncharacterised phospho-ubiquitin as distinct nuclear foci after induction of DNA damage. I then demonstrate that this modification has a role in the DNA damage response, likely as part of the repair of double strand breaks by non-homologous end joining, non-phosphorylatable mutants of ubiquitin show reduced recruitment of 53BP1 to damage sites. This mutant causes no alteration to cell viability or cell cycle in unperturbed cells, but shows resistance to ionising radiation. Finally I show that foci formation by this modification is regulated through canonical DSB proteins, and is a novel factor in the double strand break response.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):