BLM-Driven Recombination at Alternative Lengthening of Telomeres and Non-Telomeric Sites

About This Grant

Abstract Telomeres are repetitive DNA sequences that protect chromosome ends. Telomeres become shorter with each cell division due to the end replication problem, and thus their maintenance is essential for cellular immortality in cancer. While most cancers reactivate telomerase, approximately 15% use an alternative mechanism known as Alternative Lengthening of Telomeres (ALT), which relies on homology-directed DNA repair. The precise molecular mechanisms that initiate and regulate ALT remain poorly understood, limiting the development of targeted therapies. My recent study revealed that the Bloom syndrome helicase (BLM) plays a central role in initiating ALT by unwinding lagging strand DNA. In addition, depletion of BLM rescues the lethal telomeric recombination induced by the loss of the DNA translocase FANCM specifically in ALT-positive cells. FANCM associates with ALT telomeres in a BLM helicase dependent manner, suggesting that BLM promotes the formation of toxic intermediates that FANCM must resolve. Building on these findings, this project aims to elucidate the molecular mechanism by which BLM and FANCM co-regulate ALT and to understand how the loss of the FANCM—the most essential target in ALT-positive cancers—redirects ALT-associated DNA repair into a toxic pathway (Aim1). Furthermore, I will investigate whether BLM-driven recombination events extend beyond telomeres and contribute to genome instability at non-telomeric sites (Aim2). Together, these studies will define the (1) upstream signals and DNA structures that initiate recombination during ALT, (2) how FANCM loss induces toxic telomeric recombination, and (3) broader roles for BLM in genome-wide recombination and genome instability. By integrating genetic, biochemical, molecular, genomic and cell biological approaches, this research will provide novel insights into the regulation of ALT and its impact on genome stability. These discoveries may guide the development of targeted therapeutic strategies for ALT- positive cancers, as well as other cancers that rely on BLM-directed recombination for survival. Importantly, successful completion of these aims will equip me with a versatile toolkit of unbiased approaches to investigate genome instability and will lay the foundation for establishing my independent research program.