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Defining the role of UBLylation pathways in the DNA damage response


Project Description

Posttranslational modification with ubiquitin-like proteins (UBLs) is fundamental to most aspects of eukaryotic cell biology. Similarly to ubiquitin UBLs can be added to substrate proteins, a process known as UBLylation, through an enzymatic cascade involving a UBL-activating E1 enzyme, an E2-conjugating enzyme and an E3 ligase. Like ubiquitin, UBLs can be added as a single moiety or as chains of varying topologies to one or several substrate residues. Recently, several UBLs have been shown to promote genome stability through the DNA damage response (DDR). However, most of the ~15 UBLs encoded in the human genome remain understudied in this regard, which is surprising considering the importance of UBLs and the DDR for human health, particularly regarding healthy ageing: defective UBL networks, as well as accumulation of DNA damage, are linked to various age-related diseases, such as cancer and neurodegeneration. Thus, in order to optimally exploit UBL systems for therapeutic purposes, there is a pressing need to gain mechanistic insights into novel UBLylation pathways. To address this limitation, the project aims to unravel novel UBLylation pathways in the DDR. The work will integrate innovative cross-disciplinary approaches and technologies that can be widely applied, such as cutting-edge proteomic, biophysical, structural, and state-of-the-art imaging methods, as well as DNA repair assays and tissue culture. Moreover, the project involves an innovative chemical biology technique to identify transient protein-protein interactions common to UBL cascades, and a 3-month visit to AstraZeneca in Cambridge to join one of their DDR teams led by Dr Josep Forment. By identifying novel UBLylation pathways important for the DDR, the project will impact on multiple cell biology areas. In the longer run, the findings could aid the design of therapeutic strategies to treat and/or prevent diseases linked to faulty UBL networks to promote healthy ageing.

Entry Requirements
Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in cell biology, biochemistry or a related subject. A Masters degree in a relevant subject area and/or experience in the DNA damage response and ubiquitin/ubiquitin-like fields is desirable.

Funding Notes

BBSRC CTP Studentship with AstraZeneca. Studentship funding is for a duration of four years commencing in September 2019 and covers UK/EU tuition fees and an annual RCUK stipend currently £14777 for 18/19. On the online application form select PhD Cell Biology.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit

References

1. Schmidt, C. K. et al. Systematic E2 screening reveals a UBE2D–RNF138–CtIP axis promoting DNA repair. Nat. Cell Biol. 17, 1458–1470 (2015).
2. Balmus, G. et al. ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks. bioRxiv 330043 (2018). doi:10.1101/330043
3. Schwertman, P., Bekker-Jensen, S. & Mailand, N. Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers. Nat. Rev. Mol. Cell Biol. 17, 379–394 (2016).

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