The function of human PIF1 in G quadruplex formation and replication stress response at ALT telomeres
Year: 2026
Type: preprint
Abstract: Cancers maintain their telomeres through two telomere maintenance mechanisms: 85-90% of cancers rely on telomerase (TEL+), while 10-15% of cancers adopt the Alternative Lengthening of Telomeres (ALT) pathway. The Break-Induced Replication (BIR) pathway plays a critical role in maintaining telomere length in the ALT+ cells. In both yeast and human, PIF1, a 5’ to 3’ helicase, is required for the robust activity of BIR. However, the extent of human PIF1 (hPIF1) involvement in the ALT pathway remains unknown. Here we showed that hPIF1 can be recruited to damaged telomeres in ALT+ cells. In addition, we demonstrated that inhibition of hPIF1 induced DNA damage and G quadruplex (G4) accumulation at ALT telomeres, leading to a moderate reduction of the mean telomere length. Most interestingly, we demonstrated that inhibition of hPIF1 also attenuates checkpoint activation, BLM recruitment, single-stranded DNA (ssDNA) formation, DNA damage, and G4s at telomeres in the FANCM deficient ALT+ cells. Finally, we showed that inactivation of hPIF1 affects the viability of both ALT+ and TEL+ cancers, suggesting that hPIF1 is a potential drug target for cancer therapy.
Authors: Ashwin Ragupathi, Rongwei Zhao, Shakir Najit, Anthony Fernandez, Heba Abid, Jiho Mo, Samantha Juang, Christopher Tong, Derin I. Yetil, Liam Buchanan, Connor McDowell, Lindsay Mosca, Bronwyn Kelly, Rebecca Kelly, Zakir Hossain, Subhabrata Chaudhury, Jaewon Min, Huaiying Zhang, Ming Xiao, Binghui Shen, Dong Zhang
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204918639
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