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Targeting telomere maintenance and repair in cancer.

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  • Full or part time
    Dr D Clynes
    Dr A Blackford
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

THE PROJECT
Cancer occurs through the uncontrolled division of cells. The number of times a cell can divide is limited by the length of specialised DNA sequences found at the end of chromosomes called telomeres. For a cell to become cancerous it has to stop its telomeres from shortening.

To accomplish this, cancer cells either activate an enzyme (telomerase), or they copy telomeric sequences from the end of one DNA molecule to another (the alternative lengthening of telomeres (ALT) pathway).

Importantly, it is predicted that ALT positive cancers are more susceptible to different therapeutic treatments than other cancers but to date there are no ALT-targeted therapeutics. Recent research has provided important clues as to how telomere lengthening is activated in ALT cancers. We have shown that expression of a protein ATRX, which is inactivated in most ALT cancers1, suppresses telomere lengthening in ALT cells2. The mechanism by which ATRX loss leads to induction of ALT remains contentious, however, our recent data suggests that this may be linked to a role for ATRX in facilitating DNA replication at telomeres. This project will aim to address this possibility further using a combination of genetic and proteomic based approaches. Moreover, the development of genetic and small molecule screens will be used to a) determine additional factors involved in facilitating telomeric DNA replication and b) develop new ways to target ALT cancer cells.

THE TRAINING
This studentship will provide training in a variety of techniques including: cutting edge microscopy and genome editing using CRISPR-Cas9 technology.

PUBLICATIONS
Clynes et al., 2015. Suppression of the Alternative Lengthening of Telomere pathway by the chromatin remodeling factor ATRX. Nature Communications 6 7538

Lovejoy et al., 2012. Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway. PloS Genetics 8(7) e1002772

Funding Notes

All complete applications received by 12 noon (UK time) on Friday 10 January 2020 will automatically be considered for all relevant competitive University and funding opportunities, including the Clarendon Fund, Medical Research Council funding, and various College funds. Please refer to the Funding and Costs webpage (https://www.ox.ac.uk/admissions/graduate/courses/dphil-oncology) for this course for further details relating to funded scholarships and divisional funding opportunities.

Funded studentships are highly competitive and are awarded to the highest ranked applicant(s) based on the advertised entry requirements for each programme of study.

References

Whilst you must register three referees, the department may start the assessment of your application if two of the three references are submitted by the course deadline and your application is otherwise complete. Please note that you may still be required to ensure your third referee supplies a reference for consideration.

Academic references are strongly encouraged, though you may use up to one professional reference provided that it is relevant to the course.

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FTE Category A staff submitted: 238.51

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