Targetting telomeric transcription as a potential cancer therapy 

Supervisors: Dr David Clynes, Prof Richard Gibbons, Prof Peter McHugh

Project Overview
To divide indefinitely, tumour cells must maintain the length of their chromosome ends (telomeres). In the majority of tumours this is facilitated through the up regulation of telomerase. 15% of cancers, however, achieve immortality via an alternative, telomerase-independent mechanism, the so-called ALT pathway, which is thought to involve the recombination mediated copying of telomeric templates. It has recently become evident that many paediatric cancers are associated with an active ALT pathway, including several soft tissue cancers and cancers of the central nervous system. One implication is that it may be beneficial to tailor treatments depending on the ALT status of the cancer. The development of novel therapies has so far been limited by a poor understanding of the molecular details governing the ALT pathway. Recent insights, however, provide promising leads for future research. Of note, the telomeres of ALT cancer cells have been found to exhibit a more relaxed chromatin structure, coincident with increased transcription of the long non-coding RNA ‘TERRA’. Interestingly, TERRA has been shown to form RNA:DNA hybrid structures at telomeres, known a R-loops which may promote telomeric recombination.

The proposed project aims to determine what facilitates the increases in TERRA transcription observed in these cancers and whether targeting this transcript could potentially be used as a therapeutic strategy.

This will be addressed using a combination of newly available, cutting edge technologies including the use of a re-purposed CRISPR/Cas system (CRISPRi) that can suppress transcription at defined genomic targets and LNA GapmeR technology to specifically ablate telomeric RNA transcripts.

Training Opportunities
Molecular and cell biology skills
Designing and validating site specific nucleases
Confocal and widefield microscopy

Theme
DNA repair, Cancer, Epigenetics

References

  1. RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells. Arora, R. et al., Nat Commun. 2014 5 5220
  2. Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway. Lovejoy et al., Plos Genet 7(8) e1002772
  3. Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX. Clynes et al., Nat Commun. 2015 6 7538

 For further information, please contact david.clynes@oncology.ox.ac.uk