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Identifying and targeting aberrant DNA repair in cancers with dysfunctional telomeres


   Cardiff School of Medicine

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  Prof D Baird, Prof S Reed, Dr Kate Liddiard  No more applications being accepted  Self-Funded PhD Students Only

About the Project

Cancer mutations result from DNA repair responses to genomic damage provoked by a diversity of environmental and cell-intrinsic insults and stresses.

Our lab is interested in the origins of cancer and the contributions of dysfunctional telomeres to oncogenesis. Telomeres shorten as a function of natural cell division until they become too short to provide ongoing protection of coding sequences close to the chromosome termini. Cells that fail to cease proliferating at this critical telomere length can enter a state of telomere-driven crisis – an episode of exacerbated cellular stress during which short telomeres can fuse and initiate gross genomic recombinations. We have previously established essential roles for non-homologous end-joining DNA repair components in telomere fusion, paving the way for novel therapeutic interventions that modulate the functions of these specific factors. Our research team has also developed innovative genomics sequencing and bioinformatics approaches to characterise telomere fusions within patient DNA. Rational targeting in tandem with personalised sequencing will enable selection of the most appropriate treatment regimens for cancer patients, enhancing survival rates and mitigating the socioeconomic burden of unproductive therapies.

This PhD will focus on the contributions of DNA polymerase theta (POLQ) to cancer evolution, aiming to delineate key features and vulnerabilities of POLQ-mediated DNA repair that can targeted therapeutically.

POLQ is involved in DNA synthesis at double-strand breaks that cannot be repaired by homologous recombination (HR), resulting in genetic mutations and deletions that can be detected by DNA sequencing. Elevated POLQ expression has been detected in cancers with defective HR DNA repair, where targeting this compensatory survival mechanism may produce selective tumour cell death. Novel pharmaceutical POLQ inhibitors will imminently enter clinical trials for the treatment of breast, ovarian, pancreatic and prostate cancer patients with mutations in HR DNA repair genes, including BRCA1 and BRCA2. In a parallel exciting development, the antibiotic, novobiocin, has been rediscovered as an effective POLQ inhibitor during a systematic screen to identify therapeutic agents that overcome drug resistance. Modulation of POLQ activity and expression is, therefore, already clinically achievable and urgently demands additional qualification in diverse cancer models and conditions.

This project will aim to explore the validity of POLQ as a therapeutic target in HR-deficient and other cancers within the context of telomere dysfunction.

The student will gain experience in a broad range of molecular biology and cell culture techniques. In addition, they will utilise our single molecule approaches to characterise telomere fusions with high-throughput long-read DNA sequencing, as well as whole genome sequencing.

Keywords

Telomere, BRCA

Application Process

We are seeking enthusiastic and motivated students with an interest in Cancer or genomic research. Applicants should possess a minimum of an upper second-class Honours degree, master's degree, or equivalent in a relevant subject.

Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)

Following discussion with proposed supervisors and to be considered you must submit a formal application via Cardiff University’s online application service. Medicine - Study - Cardiff University

The total duration of this PhD programme is 4 years. There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (i.e. October 2022). This will take you to the application portal.

In the ‘Research Proposal’ section of the application enter the name of the project you are applying to.

Candidates must submit the following information:

  • Supporting statement 
  • CV 
  • Qualification certificates 
  • Proof of Funding i.e. a letter of intent from your sponsor or confirmation of self-funded status.
  • References x 2 
  • Proof of English language (if applicable)

Closing date for applicants is 31st March 2022.


Funding Notes

This is a Self-Funded/Sponsored PhD opportunity.
FUNDING REQUIRED:
Full UK/EU or International Tuition Fees
UK Living Expenses
Bench Fees (where applicable)
Open to all students of any nationality without restrictions (UK/EU and International)
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