Alternative Lengthening of Telomeres

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.

• Examining the interplay between BITS and other DNA repair processes engaging ALT telomeres.
• Elucidating the molecular mechanisms of BLM-mediated telomere clustering.
• Determining how DNA replication and repair impact ALT telomere sequence by NanoPore sequencing.

Broderick, R. et al. Pathway choice in the alternative telomere lengthening in neoplasia is dictated by replication fork processing mediated by EXD2’s nuclease activity. Nature Communications 14, 2428 (2023).

Nieminuszczy, J.*, Broderick, R.*, et al.EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2. Molecular Cell 75, 605-619.e606 (2019). *Joint first authorship

Broderick, R. et al.EXD2 promotes homologous recombination by facilitating DNA end resection. Nature Cell Biology 18, 271-280 (2016).

Broderick, R., Nieminuszczy, J., Blackford, A.N., Winczura, A. & Niedzwiedz, W. TOPBP1 recruits TOP2A to ultra-fine anaphase bridges to aid in their resolution. Nature Communications 6, 6572 (2015).

Lai, X., Broderick, R., et al.MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells. Nature Communications 8, 15983 (2017).