PhD Studentship: Understanding and exploiting poly(ADP-ribose) glycohydrolase inhibitors for cancer

Upon DNA binding the poly(ADP-ribose) polymerase family of enzymes (PARPs) add multiple ADP-ribose subunits to themselves and other acceptor proteins. Inhibitors of PARPs have become an exciting and real prospect for monotherapy and as sensitizers to ionising radiation (IR). The action of PARPs are reversed by poly(ADP-ribose) glycohydrolase (PARG). Until recently studies of PARG have been limited by the lack of an inhibitor. Such an inhibitor is now available and we have recently published a screen of the synthetic lethal partners of PARG and the ability of PARG inhibitors to radiosensitize.

Those drugs generally considered “PARP inhibitors” are to large degree PARP1 and PARP2 inhibitors and are thought to work by inhibiting DNA repair. However the PARPs are a large family of proteins, and PARG is predicted to not only to reverse the activity of PARP1 and PARP2 during DNA repair but also the action of PARP3 and PARP5a/b; both of which play roles in mitosis. Further PARP5a/b is involved in wnt signaling and telomere maintenance.

Here the student will follow up the recent publications by looking at some of the questions that were left unanswered i.e why do some of the synthetic lethal relationships exist?, why in come cases do PARG inhibitors have a greater chemosensitizing effect than PARP inhibitors? and what functions does PARG have outside of reversal of PARP1 and PARP3 action in DNA repair.

The proposed project will be carried out in the Department of Oncology & Metabolism, The University of Sheffield, UK. Sheffield offers a unique combination of infrastructure and expertise for the planned project. The University of Sheffield is a Centre of Excellence for Nucleic Acids Research which means that there are unique and unrivalled facilities in Sheffield for carrying out studies in the area of Genome biology which the University has committed to continuously support and expand. This will warrant students who are interested in this project to acquire special techniques and skills in genome biology, as well as a broad spectrum of techniques in the fields of cancer biology, cell and molecular biology, and biochemistry.

http://genome.sheffield.ac.uk/

 

Funding Notes

Start:

September 2018

Qualifications criteria:

Applicants applying for studentship must have obtained, or will soon obtain, a first or good upper-second class UK honours degree or equivalent non-UK qualifications, in an appropriate science/technology area.

Residence criteria:

Grant provides tuition fees and stipend of at least £14,553 (RCUK rate 2017/18) for UK and EU nationals that meet all required eligibility criteria.

References

1. Gravells P, Neale J, Grant E, Nathubhai A, Smith KM, James DI, Bryant HE. Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib. DNA Repair (Amst). 2017 Nov 22;61:25-36. doi: 10.1016/j.dnarep.2017.11.004. [Epub ahead of print] PubMed PMID: 29179156.
2. Gravells P, Grant E, Smith KM, James DI, Bryant HE. Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase. DNA Repair (Amst). 2017 Apr;52:81-91. doi: 10.1016/j.dnarep.2017.02.010. Epub 2017 Feb 17. PubMed PMID: 28254358; PubMed Central PMCID: PMC5360195.