4-YEAR DPhil/PhD Studentship: Defining novel DNA repair mechanisms to target in breast cancer treatment
Department of Biochemistry, University of Oxford
Main academic supervisor: Professor Nick Lakin
Please quote Studentship Code: D32
Maintaining genome integrity through DNA repair is critical to guard against a variety of diseases, including cancer. Our research aims to understand these processes, with specific reference to how Poly(ADP-ribose) polymerases (PARPs) regulate genome stability.
PARPs are a cornerstone of the DNA damage response that signal DNA damage to facilitate its repair by modifying proteins with ADP-ribose – a process known as ADP-ribosylation. Agents that inhibit this activity (PARP inhibitors) have emerged as key agents in cancer therapy, particularly to treat breast and ovarian tumours. However, the response of tumours is variable and multiple resistance mechanisms have been identified. The mechanistic basis of these processes, including how PARPs regulate multiple DNA repair mechanisms, is poorly understood.
This research aims to address these important questions. Our recent data point to a critical role for PARPs in regulating repair during DNA replication. This project will combine cutting edge genome editing and proteomic approaches with a variety of cell biology techniques to decipher how PARPs regulate replication-associated repair, including the substrates that they modify with ADP-ribose. Our long term vision is to exploit this knowledge to identify biomarkers that predict whether a patient will respond to PARP inhibitors, in addition to mechanisms to target in PARP inhibitor-resistant tumours.
Our previous work identified substrates ADP-ribosylated by PARPs during DNA replication and discovered that these events are critical for repair of damaged replication forks by homologous recombination. Building on these key conceptual advances the student will:
a) Define the HR pathway that is regulated by PARPs to repair replication forks.
b) Characterise the role of ADP-ribosylation targets in this pathway and how they promote survival of breast cancer cells.
Training will be provided in all experimental approaches that are key to the project. This includes generation of gene disruption and replacement cell lines using cutting edge CRISPR/Cas9 genome editing technology, expression of wild-type and mutant proteins, and microscopy based assays to assess the DNA damage response and replication dynamics in cells. A variety of other cell based approaches will also be employed to investigate DNA repair function.
The student will also be provided with a thorough training in all other aspects of conducting scientific research including experimental design, data evaluation, keeping laboratory records, scientific writing, oral presentations etc.
The scholarship covers course fees (at the Home fee rate), living cost allowance of not less than £19,000 per annum for up to four years and funds for conference travel. The scholarship is funded by Breast Cancer Now and the Department of Biochemistry.
Eligibility: we welcome applications from UK applicants.
Students with a molecular biology, cell biology or biochemistry background, ideally with some relevant practical undergraduate experience, would be preferred.
Informal enquiries are welcome: email@example.com
To apply for this funded studentship, please submit an online application to the University of Oxford Apply online or admission to the D.Phil. in Biochemistry (course code: RD_BC1) by the deadline 12noon Friday, 24th February 2023. It is very important that you quote Studentship Code D32. No research proposal is required as part of the application. Instead you are required to upload a personal statement of no more than 500 words (describing your motivation and aptitude for this position), your CV, and official transcripts of your undergraduate marks and degree. Please arrange that three referees directly submit references for you. Full details on how to apply can be found at: https://www.ox.ac.uk/admissions/graduate/courses/dphil-biochemistry?wssl=1