The function of human PIF1 in G quadruplex formation and replication stress response at ALT telomeres

The function of human PIF1 in G quadruplex formation and replication stress response at ALT telomeres is a crucial area of study. Cancers maintain their telomeres through two mechanisms: the majority rely on telomerase, while a smaller percentage use the Alternative Lengthening of Telomeres (ALT) pathway. The Break-Induced Replication (BIR) pathway is crucial for maintaining telomere length in ALT+ cells.

PIF1, a 5 to 3 helicase, is required for robust BIR activity in both yeast and human cells. However, its role in the ALT pathway in humans is not well understood. This study revealed that hPIF1 can be recruited to damaged telomeres in ALT+ cells. Inhibiting hPIF1 resulted in DNA damage and G quadruplex (G4) accumulation at ALT telomeres, causing a moderate decrease in mean telomere length.

Interestingly, hPIF1 inhibition also reduced checkpoint activation, BLM recruitment, single-stranded DNA (ssDNA) formation, DNA damage, and G4 formation at telomeres in FANCM deficient ALT+ cells. Lastly, the study indicated that inactivating hPIF1 affects the viability of both ALT+ and telomerase-reliant cancers, suggesting that hPIF1 could be a potential drug target for cancer therapy.