RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening

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 Noth, Fernando J. Martinez, Gregory A. Petsko and Laurie H. Glimcher ()
Additional contact information
Shrestha Ghosh: Dana-Farber Cancer Institute, Harvard Medical School
Mileena T. Nguyen: Dana-Farber Cancer Institute, Harvard Medical School
Ha Eun Choi: Dana-Farber Cancer Institute, Harvard Medical School
Maximilian Stahl: Dana-Farber Cancer Institute
Annemarie Luise Kühn: University Medicine Greifswald
Sandra Auwera: University Medicine Greifswald
Hans J. Grabe: University Medicine Greifswald
Henry Völzke: University Medicine 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

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51336-3

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