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Metabolic constraint of human telomere length by nucleotide salvage efficiency

Author

Listed:
  • William Mannherz

    (Boston Children’s Hospital
    Dana-Farber Cancer Institute
    Harvard Medical School
    Harvard Medical School)

  • Andrew Crompton

    (Boston Children’s Hospital
    Dana-Farber Cancer Institute
    Harvard Medical School
    Harvard Medical School)

  • Noah Lampl

    (Boston Children’s Hospital
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Suneet Agarwal

    (Boston Children’s Hospital
    Dana-Farber Cancer Institute
    Harvard Medical School
    Harvard Medical School)

Abstract

Human telomere length is tightly regulated and associated with diseases at either extreme, but how these bounds are established remains incompletely understood. Here, we developed a rapid cell-based telomere synthesis assay and found that nucleoside salvage bidirectionally constrains human telomere length. Metabolism of deoxyguanosine (dG) or guanosine via purine nucleoside phosphorylase (PNP) and hypoxanthine-guanine phosphoribosyltransferase to form guanine ribonucleotides strongly inhibited telomerase and shortened telomeres. Conversely, salvage of dG to its nucleotide forms via deoxycytidine kinase drove potent telomerase activation, the extent of which was controlled by the dNTPase SAMHD1. Circumventing limits on salvage by expressing Drosophila melanogaster deoxynucleoside kinase or augmenting dG metabolism using the PNP inhibitor ulodesine robustly lengthened telomeres in human cells, including those from patients with lethal telomere diseases. Our results provide an updated paradigm for telomere length control, wherein telomerase reverse transcriptase activity is actively and bidirectionally constrained by the availability of its dNTP substrates, in a manner that may be therapeutically actionable.

Suggested Citation

  • William Mannherz & Andrew Crompton & Noah Lampl & Suneet Agarwal, 2025. "Metabolic constraint of human telomere length by nucleotide salvage efficiency," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58221-7
    DOI: 10.1038/s41467-025-58221-7
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    References listed on IDEAS

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    1. Cheng-Yong Tham & LaiFong Poon & TingDong Yan & Javier Yu Peng Koh & Muhammad Khairul Ramlee & Vania Swee Imm Teoh & Suihan Zhang & Yi Cai & Zebin Hong & Gina S. Lee & Jin Liu & Hai Wei Song & William, 2023. "High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Suneet Agarwal & Yuin-Han Loh & Erin M. McLoughlin & Junjiu Huang & In-Hyun Park & Justine D. Miller & Hongguang Huo & Maja Okuka & Rosana Maria dos Reis & Sabine Loewer & Huck-Hui Ng & David L. Keefe, 2010. "Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients," Nature, Nature, vol. 464(7286), pages 292-296, March.
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