FANCM suppresses ALT activity by modulating BLM-TOP3a-RMI complex activity at telomeres
Children’s Medical Research Institute.
The collapse of stalled replication forks is one of the major drivers of genomic instability, and cells have evolved committed mechanisms to overcome replication stress. These pathways are particularly pertinent at telomeres, which are long terminal repetitive DNA regions that are intrinsically prone to replication fork slowing, stalling and breakage. Cancer cells that use the Alternative Lengthening of Telomeres (ALT) pathway of telomere maintenance display elevated levels of telomere-specific replication stress, and it is thought that ALT cells utilise these degenerate sites as substrates for break-induced telomere synthesis events. FANCM is a multifunctional protein that is central to the Fanconi anaemia (FA) core complex, and can independently bind to the BLM-TOP3A-RMI (BTR) complex. We demonstrate that FANCM depletion provokes excessive ALT activity, evident by rapid induction of extrachromosomal telomeric repeat (ECTR) DNA, and increased firing of break-induced telomere synthesis events. This culminates in an ALT-specific G2/M arrest and loss of cell viability. The MM2 domain of FANCM, which binds the BTR complex, suppresses this response, suggesting that ALT activity is attenuated by FANCM-BTR-mediated replication fork remodelling, and that collapsed replication forks instigate ALT-mediated telomere synthesis events.