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Nominating Supervisor: David Clynes

Second Supervisor: Andrew Blackford

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