To survive, cancer cells must protect the ends of their chromosomes—and about 10–15% of cancers, including aggressive brain tumours called high-grade gliomas, do this using a backup system called the Alternative Lengthening of Telomeres (ALT) mechanism. There are currently no effective treatments for these ALT-reliant cancers. This project aims to fill that gap by answering three fundamental questions about how ALT works: how it coordinates with other DNA repair processes, how it brings telomeres together to trigger elongation, and how that process changes the telomere’s DNA sequence. If successful, the research could identify new drug targets—specific proteins or interactions that can be blocked to selectively kill ALT-reliant cancer cells. It may also uncover biomarkers that allow doctors to diagnose or stratify these cancers, improving treatment decisions for patients with high-grade glioma and other ALT-positive tumours. The work is primarily fundamental science, probing the basic biology of DNA repair and replication. But understanding these core processes has historically led to unexpected clinical breakthroughs—and here, the path to therapies is unusually direct, because the mechanism itself is a clear vulnerability in a subset of hard-to-treat cancers.
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BACKGROUND AND IMPORTANCE: To survive and proliferate, cancer cells must maintain the DNA at the ends of their chromosomes, called telomeres, which are comprised of long arrays of repetitive DNA sequences. In normal cells, these sequences shorten each time the cell divides, limiting the cell’s lifespan. Cancer cells maintain these sequences to grow indefinitely. Therefore, targeting the mechanisms of telomere maintenance represents a likely strategy to selectively kill cancer cells. Most cancers maintain their telomeres via a protein called telomerase. However, 10-15% of cancers engage the Alternative Lengthening of Telomeres (ALT) mechanism. There are currently no useful treatments for ALT-reliant cancers, which include brain tumours such as aggressive high-grade glioma. Moreover, the identification of biomarkers for the diagnosis and stratification of ALT-reliant cancers are sorely needed. Therefore, understanding the ALT mechanism will lead to therapies to treat ALT-reliant cancers, including high-grade glioma. ALT-reliant cancers utilise a DNA repair mechanism at clustered telomeres to mediate telomere elongation called break-induced telomere synthesis (BITS). While some progress has been made regarding the ALT molecular mechanism, several key questions remain: 1. How is BITS coordinated with other DNA repair processes? 2. How is BITS engaged at clustered telomeres? 3. How does DNA replication and repair during BITS influence telomere length and sequence composition? Answering these questions will elucidate the molecular mechanisms of ALT and the processes of replication fork stability and DNA-repair pathway choice in human cells. Moreover, drugging components of the ALT machinery and/or exploiting synthetic sick phenotypes between factors promoting ALT and other DNA repair processes represents a likely strategy to kill ALT-reliant cancers. Therefore, this work may improve patient outcomes for ALT-reliant cancer sufferers, including high-grade glioma patients. I will answer the above key questions via three interconnected yet independent research objectives: OBJECTIVES: Define the interplay of BITS with other DNA repair mechanisms. Reveal the mechanisms of ALT telomere clustering. Determine how ALT telomere replication and repair impact telomere sequence. OUTCOME: Objective 1 will determine the contribution of Microhomology-Mediated End-Joining (MMEJ) to ALT telomere maintenance (my data suggests MMEJ engages ALT+ telomeres) and will establish the genetic relationships between BITS and MMEJ in the context of ALT. This work will extend our understanding of the factors required to promote ALT cancer cell survival and will identify therapeutic targets for the design of small molecule inhibitors to treat ALT-reliant cancers. Objective 2 will uncover the molecular mechanisms of telomere clustering crucial to ALT engagement and will determine moieties of the BLM and SMC5/6 proteins required to promote clustering which may be targeted for inhibition to selectively eliminate ALT-reliant cancers. Moreover, this objective will determine if clinically relevant drugs impact telomere clustering and therefore may represent effective treatments for ALT+ cancers. Objective 3 will determine the impact of replication fork progression, collapse, and subsequent repair on telomere sequence in both ALT-reliant and telomerase-positive cells. This will uncover the molecular origins of “telomere variant sequences” associated with ALT engagement and may uncover biomarkers to diagnose and/or stratify ALT-reliant cancers. Collectively, this work will shed light on the fundamental biological processes of DNA replication, DNA double-strand break repair and telomere maintenance and may uncover therapeutic targets and biomarkers for the treatment of ALT-reliant cancers including high-grade glioma, benefiting cancer patients, the NHS and other equivalent health services worldwide.
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