Coordination of ALT telomere maintenance across the cell cycle

Approximately 10%-15% of human cancers maintain their telomeres through alternative lengthening of telomeres (ALT), a recombination-based pathway that exploits chronic telomeric replication stress to drive telomere elongation. Although initiated in S phase, ALT-associated telomere synthesis is prominent in G2 phase and can extend into mitosis through mitotic DNA synthesis (MiDAS) and even into G1 phase of the next cell generation through post-mitotic DNA synthesis (post-MiDAS). Here, we review recent advances in the mechanistic understanding of ALT across the cell cycle. We emphasize how persistent replication stress and elevated DNA damage at telomeres drive ALT activity but must be tightly controlled to preserve telomere integrity and cell viability. We further highlight how MiDAS and post-MiDAS may act as last-resort pathways to preserve genome integrity when under-replicated telomeres bypass cell cycle checkpoints. Finally, we discuss how these mechanistic insights could be leveraged to develop novel therapeutic strategies specifically targeting ALT-dependent cancers.