Telomere maintenance pathways and their role in genome stability.

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Most cancer cells have the capacity to replicate indefinitely. This is partly achieved by activation of a telomere maintenance mechanism (TMM) and we are trying to understand the molecular basis of some of these pathways. Telomeres are repetitive DNA sequences that cap chromosomes and so prevent damage to the genome. The majority of tumours activate telomerase or the Alternative Lengthening of Telomeres (ALT) pathway to maintain telomeres but the TMM is unknown in a subset of tumours. In addition the molecular mechanism that underlies ALT is poorly understood. Recently we have shown that activation of the ALT pathway can destabilize other repeated sequences in the genome but the significance of this observation is unclear. Therefore using single telomere and single molecule approaches we plan to investigate telomeric DNA and other sequences in order to elucidate the underlying TMM in tumours. In addition in cell lines we plan to disrupt the expression of genes that are thought to play a role in ALT and study the effect on telomeres and other DNA sequences in the genome. In the long term we hope this will lead to identification of targets for novel anti-cancer therapies.