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RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening

Author

Listed:
  • Shrestha Ghosh

    (Dana-Farber Cancer Institute, Harvard Medical School
    Harvard Medical School)

  • Mileena T. Nguyen

    (Dana-Farber Cancer Institute, Harvard Medical School
    Yale University)

  • Ha Eun Choi

    (Dana-Farber Cancer Institute, Harvard Medical School)

  • Maximilian Stahl

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Annemarie Luise Kühn

    (University Medicine Greifswald)

  • Sandra Auwera

    (University Medicine Greifswald
    Site Rostock/Greifswald)

  • Hans J. Grabe

    (University Medicine Greifswald
    Site Rostock/Greifswald)

  • Henry Völzke

    (University Medicine Greifswald
    Partner Site Greifswald)

  • Georg Homuth

    (University Medicine Greifswald)

  • Samuel A. Myers

    (La Jolla Institute for Immunology)

  • Cory M. Hogaboam

    (Cedars-Sinai Medical Center)

  • Imre Noth

    (University of Virginia)

  • Fernando J. Martinez

    (Weill Cornell Medicine)

  • Gregory A. Petsko

    (Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School)

  • Laurie H. Glimcher

    (Dana-Farber Cancer Institute, Harvard Medical School
    Harvard Medical School
    Harvard Medical School)

Abstract

Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Suggested Citation

  • Shrestha Ghosh & Mileena T. Nguyen & Ha Eun Choi & Maximilian Stahl & Annemarie Luise Kühn & Sandra Auwera & Hans J. Grabe & Henry Völzke & Georg Homuth & Samuel A. Myers & Cory M. Hogaboam & Imre Not, 2024. "RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51336-3
    DOI: 10.1038/s41467-024-51336-3
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    References listed on IDEAS

    as
    1. Michael Ameismeier & Jingdong Cheng & Otto Berninghausen & Roland Beckmann, 2018. "Visualizing late states of human 40S ribosomal subunit maturation," Nature, Nature, vol. 558(7709), pages 249-253, June.
    2. Marta Markiewicz-Potoczny & Anastasia Lobanova & Anisha M. Loeb & Oktay Kirak & Teresa Olbrich & Sergio Ruiz & Eros Lazzerini Denchi, 2021. "TRF2-mediated telomere protection is dispensable in pluripotent stem cells," Nature, Nature, vol. 589(7840), pages 110-115, January.
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