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Alternative Lengthening of Telomeres

Group leader: Dr Ronan Broderick

Overview

The Alternative Lengthening of Telomeres (ALT) is a telomere maintenance mechanism that promotes the survival of 10-15% of all cancers, including high-grade glioma. By understanding how DNA replication and repair processes underpin ALT, we may identify therapeutic targets and biomarkers to aid the treatment and/or diagnosis of ALT-reliant cancers, particularly high-grade glioma.

Our research group

Telomeres are arrays of repetitive DNA sequences at the ends of our chromosomes which shorten each time our cells divide, thereby limiting the cell’s lifespan. All cancer must maintain their telomere length to achieve replicative immortality. The Alternative Lengthening of Telomeres is a homologous-recombination-based process utilised by 10-15% of all cancers to maintain their telomeres. There are currently no useful treatments for these cancers, which include a large percentage of high-grade glioma. 

Mechanistically, ALT is underpinned by DNA replication fork stability and DNA repair processes, whereby DNA breaks caused by collapsed telomeric DNA replication forks are clustered together at specialised sub-nuclear bodies, engaging a process called Break-Induced Telomere Synthesis (BITS) to maintain telomere length. Despite progress in understanding the molecular mechanisms of ALT, several key questions remain. How is BITS co-ordinated with other DNA repair mechanisms engaging ALT telomeres? What are the molecular mechanisms of telomere clustering? How does DNA replication and repair at ALT telomeres impact telomere array sequence?  To answer these questions, the Broderick lab employs a combination of cell and molecular biology techniques, advanced microscopy-based approaches and cutting edge next-generation DNA sequencing technologies. This work has the potential to identify therapeutic targets and biomarkers for the treatment/diagnosis of ALT-reliant cancers, including high-grade glioma.