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RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening.
Ghosh, Shrestha; Nguyen, Mileena T; Choi, Ha Eun; Stahl, Maximilian; Kühn, Annemarie Luise; Van der Auwera, Sandra; Grabe, Hans J; Völzke, Henry; Homuth, Georg; Myers, Samuel A; Hogaboam, Cory M; Noth, Imre; Martinez, Fernando J; Petsko, Gregory A; Glimcher, Laurie H.
Afiliación
  • Ghosh S; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Shrestha_Ghosh@dfci.harvard.edu.
  • Nguyen MT; Department of Immunology, Harvard Medical School, Boston, MA, USA. Shrestha_Ghosh@dfci.harvard.edu.
  • Choi HE; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • Stahl M; Yale University, New Haven, CT, USA.
  • Kühn AL; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • Van der Auwera S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Grabe HJ; Harvard Medical School, Boston, MA, USA.
  • Völzke H; Department for Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
  • Homuth G; Department for Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
  • Myers SA; German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
  • Hogaboam CM; Department for Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
  • Noth I; German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
  • Martinez FJ; Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
  • Petsko GA; German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany.
  • Glimcher LH; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Nat Commun ; 15(1): 7138, 2024 Aug 20.
Article en En | MEDLINE | ID: mdl-39164231
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Nucleares / Proteínas de Ciclo Celular / Telomerasa / Fibrosis Pulmonar Idiopática / Acortamiento del Telómero Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Nucleares / Proteínas de Ciclo Celular / Telomerasa / Fibrosis Pulmonar Idiopática / Acortamiento del Telómero Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido