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A persistent variant telomere sequence in a human pedigree

Author

Listed:
  • Angela M. Hinchie

    (University of Pittsburgh
    University of Pittsburgh)

  • Samantha L. Sanford

    (University of Pittsburgh
    Hillman Cancer Center)

  • Kelly E. Loughridge

    (University of Pittsburgh
    University of Pittsburgh)

  • Rachel M. Sutton

    (University of Pittsburgh
    University of Pittsburgh)

  • Anishka H. Parikh

    (University of Pittsburgh
    University of Pittsburgh)

  • Agustin A. Gil Silva

    (University of Pittsburgh
    University of Pittsburgh)

  • Daniel I. Sullivan

    (University of Pittsburgh
    University of Pittsburgh)

  • Pattra Chun-On

    (University of Pittsburgh
    University of Pittsburgh)

  • Matthew R. Morrell

    (University of Pittsburgh)

  • John F. McDyer

    (University of Pittsburgh)

  • Patricia L. Opresko

    (University of Pittsburgh
    Hillman Cancer Center
    University of Pittsburgh)

  • Jonathan K. Alder

    (University of Pittsburgh
    University of Pittsburgh)

Abstract

The telomere sequence, TTAGGG, is conserved across all vertebrates and plays an essential role in suppressing the DNA damage response by binding a set of proteins termed shelterin. Changes in the telomere sequence impair shelterin binding, initiate a DNA damage response, and are toxic to cells. Here we identify a family with a variant in the telomere template sequence of telomerase, the enzyme responsible for telomere elongation, that led to a non-canonical telomere sequence. The variant is inherited across at least one generation and one family member reports no significant medical concerns despite ~9% of their telomeres converting to the novel sequence. The variant template disrupts telomerase repeat addition processivity and decreased the binding of the telomere-binding protein POT1. Despite these disruptions, the sequence is readily incorporated into cellular chromosomes. Incorporation of a variant sequence prevents POT1-mediated inhibition of telomerase suggesting that incorporation of a variant sequence may influence telomere addition. These findings demonstrate that telomeres can tolerate substantial degeneracy while remaining functional and provide insights as to how incorporation of a non-canonical telomere sequence might alter telomere length dynamics.

Suggested Citation

  • Angela M. Hinchie & Samantha L. Sanford & Kelly E. Loughridge & Rachel M. Sutton & Anishka H. Parikh & Agustin A. Gil Silva & Daniel I. Sullivan & Pattra Chun-On & Matthew R. Morrell & John F. McDyer , 2024. "A persistent variant telomere sequence in a human pedigree," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49072-9
    DOI: 10.1038/s41467-024-49072-9
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    References listed on IDEAS

    as
    1. Diego Loayza & Titia de Lange, 2003. "POT1 as a terminal transducer of TRF1 telomere length control," Nature, Nature, vol. 423(6943), pages 1013-1018, June.
    2. Feng Wang & Elaine R. Podell & Arthur J. Zaug & Yuting Yang & Paul Baciu & Thomas R. Cech & Ming Lei, 2007. "The POT1–TPP1 telomere complex is a telomerase processivity factor," Nature, Nature, vol. 445(7127), pages 506-510, February.
    3. Lina Sieverling & Chen Hong & Sandra D. Koser & Philip Ginsbach & Kortine Kleinheinz & Barbara Hutter & Delia M. Braun & Isidro Cortés-Ciriano & Ruibin Xi & Rolf Kabbe & Peter J. Park & Roland Eils & , 2020. "Genomic footprints of activated telomere maintenance mechanisms in cancer," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    4. Tom Vulliamy & Anna Marrone & Frederick Goldman & Andrew Dearlove & Monica Bessler & Philip J. Mason & Inderjeet Dokal, 2001. "The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita," Nature, Nature, vol. 413(6854), pages 432-435, September.
    5. Jayakrishnan Nandakumar & Caitlin F. Bell & Ina Weidenfeld & Arthur J. Zaug & Leslie A. Leinwand & Thomas R. Cech, 2012. "The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity," Nature, Nature, vol. 492(7428), pages 285-289, December.
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