RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening
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.
Authors
- Imre Noth (ORCID: https://orcid.org/0000-0001-9846-5030)
- Gregory A. Petsko (ORCID: https://orcid.org/0000-0003-3668-3694)
- Maximilian Stahl (ORCID: https://orcid.org/0000-0002-1299-5901)
- Hans Jörgen Grabe (ORCID: https://orcid.org/0000-0003-3684-4208)
- Samuel A. Myers (ORCID: https://orcid.org/0000-0001-7636-0887)
- Annemarie Luise Kühn (ORCID: https://orcid.org/0000-0002-0158-8286)
- Sandra Van der Auwera (ORCID: https://orcid.org/0000-0002-1757-7768)
- Laurie H. Glimcher (ORCID: https://orcid.org/0000-0002-4971-0404)
- Mileena T. Nguyen
- Georg Homuth (ORCID: https://orcid.org/0000-0001-6839-0605)
- Cory M. Hogaboam (ORCID: https://orcid.org/0000-0003-3366-4850)
- Fernando J. Martínez (ORCID: https://orcid.org/0000-0002-2412-3182)
- Shrestha Ghosh (ORCID: https://orcid.org/0000-0003-1861-8581)
- Henry Völzke
- Ha Eun Choi
Institutions
- Cedars-Sinai Medical Center (US)
- Brigham and Women's Hospital (US)
- La Jolla Institute for Immunology (US)
- Harvard University (US)
- Cornell University (US)
- Universitätsmedizin Greifswald (DE)
- German Center for Neurodegenerative Diseases (DE)
- Yale University (US)
- Lung Institute (US)
- Dana-Farber Cancer Institute (US)
- German Centre for Cardiovascular Research (DE)
- Weill Cornell Medicine (US)
- University of Virginia (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-20
- DOI
- https://doi.org/10.1038/s41467-024-51336-3
- Citations
- 7
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 2.29
Funders
- Edward P. Evans Foundation
- Bundesministerium für Bildung und Forschung
- Universität Greifswald
- National Institutes of Health
- National Heart, Lung, and Blood Institute