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PreprintCC BYbioRxiv

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

  • A. Ragupathi
  • R. Zhao
  • S. Najit
  • A. Fernandez
  • H. Z. Abid
  • J. Mo
  • S. Juang
  • C. Tong
  • D. Yetil
  • L. Buchanan
  • C. McDowell
  • L. Mosca
9 more authors
  • B. Kelly
  • R. Kelly
  • Z. Hossain
  • S. Chaudhury
  • J. Min
  • H. Zhang1
  • M. Xiao
  • B. Shen
  • D. Zhang1
  1. 1New York Institute of Technology
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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.

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Cite

BibTeXRIS
BibTeX
@misc{ragupathi2026function,
  title = {{The function of human PIF1 in G quadruplex formation and replication stress response at ALT telomeres}},
  author = {A. Ragupathi and R. Zhao and S. Najit and A. Fernandez and H. Z. Abid and J. Mo and S. Juang and C. Tong and D. Yetil and L. Buchanan and C. McDowell and L. Mosca and B. Kelly and R. Kelly and Z. Hossain and S. Chaudhury and J. Min and H. Zhang and M. Xiao and B. Shen and D. Zhang},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.31.748286},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.31.748286v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - The function of human PIF1 in G quadruplex formation and replication stress response at ALT telomeres
AU  - A. Ragupathi
AU  - R. Zhao
AU  - S. Najit
AU  - A. Fernandez
AU  - H. Z. Abid
AU  - J. Mo
AU  - S. Juang
AU  - C. Tong
AU  - D. Yetil
AU  - L. Buchanan
AU  - C. McDowell
AU  - L. Mosca
AU  - B. Kelly
AU  - R. Kelly
AU  - Z. Hossain
AU  - S. Chaudhury
AU  - J. Min
AU  - H. Zhang
AU  - M. Xiao
AU  - B. Shen
AU  - D. Zhang
PY  - 2026
DA  - 2026/08/31
PB  - bioRxiv
DO  - 10.64898/2026.08.31.748286
UR  - https://www.biorxiv.org/content/10.64898/2026.08.31.748286v1
AB  - 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.
ER  -