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Systematic investigation of the mechanisms of replication fork protection, towards novel therapeutic strategy’

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  • Full or part time
    Dr W Niedzwiedz
    Prof J Downs
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

The Institute of Cancer Research, London, is one of the world’s most influential cancer research institutes. We are committed to attracting and developing the best minds in the world to join us in our mission—to make the discoveries that defeat cancer.

Systematic investigation of the mechanisms of replication fork protection, towards novel therapeutic strategy’

Project Description:
The ability of cells to divide enables organisms to grow and reproduce. This process requires copying and maintaining a vast amount of genetic information. Therefore, accurate replication of DNA is essential not only for the preservation of genomic integrity but also the continuation of life. To accomplish this, cells have evolved complex mechanisms to replicate cellular DNA with high fidelity. However, replication of damaged DNA templates leads to inhibition of DNA synthesis inducing replicative stress. This is important from a clinical perspective as DNA replication stress is prevalent in human precancerous lesions and may contribute to tumour progression by driving chromosomal instability in cancer cells. Moreover, many commonly used anticancer agents (e.g. camptothecin, platinum-based drugs, gemcitabine or PARP inhibitors) target the process of replication to kill cancer cells. However, the mechanism(s) by which mammalian cells mitigate replicative stress is currently unclear.
As part of my laboratory ongoing effort to address this question my laboratory performed an unbiased screen to map proteins recruited to replication forks under condition of replicative stress. This allowed us to identify and characterise several novel factors with key functions in response to replicative stress and resistance to a large number of anti-cancer treatments.
The aim of this DPhil project will be to understand the role of several novel, uncharacterized factors, identified in our screen as essential for DNA replication and cellular responses to ant-cancer treatment. This work will provide further insight into the molecular mechanisms of replication fork stability and unravel the unique vulnerabilities of cancer cells to the targeting of genetically redundant pathways. Moreover, molecular information gained from these studies could pave the way for the development of new anti-cancer therapeutic strategies.
Project Aims:
Aim 1. Proteomic pull down of a set of novel putative fork protection factors (functional proteomics).
Aim 2. Exploration of molecular mechanisms by which they promote fork stability (cell biology).
Aim 2. Screening of identified factors to explore synthetic lethal interactions within this context (gene function).
Expected outcomes
During the course of the project, the student will become proficient in a broad range of techniques, including state-of-the art CRISPR-Cas9 genome editing, super-resolution fluorescent microscopy, single molecule analysis of DNA replication and proteomics. The student will be encouraged to attend and present their work at national and international meetings, and to be involved in organizing and presenting at journal clubs and internal seminar series.
Overall, the work carried out by the successful applicant will increase our basic understanding of how cells replicate their genome with high fidelity in order to maintain genome stability, providing critical insight into the mechanistic wiring of replication fork repair with the potential to identify novel components that could be targeted therapeutically.

Funding Notes

Students receive an annual stipend, currently £21,000 per annum, as well as having tuition fees (both UK/EU and overseas) and project costs paid for the four-year duration. We are open to applications from any eligible candidates and are committed to attracting and developing the best minds in the world.
See to apply
Applications close 11:55pm UK time on Sunday 17th November 2019
Candidates must have a first class or upper second class honours BSc Honours/MSc in a relevant subject.

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