The tumor suppressor HNRNPK induces p53-dependent nucleolar stress to drive ribosomopathies
The nucleolus is a membraneless organelle and an excellent stress sensor. Any changes in its architecture or composition lead to nucleolar stress, resulting in cell cycle arrest and interruption of ribosomal activity, critical factors in aging and cancer. In this study, we identified and described the pivotal role of the RNA-binding protein HNRNPK in ribosome and nucleolar dynamics. We developed an in vitro model of endogenous HNRNPK overexpression and an in vivo mouse model of ubiquitous HNRNPK overexpression. These models showed disruptions in translation as the HNRNPK overexpression caused alterations in the nucleolar structure, resulting in p53-dependent nucleolar stress, cell cycle arrest, senescence, and bone marrow failure phenotype, similar to what is observed in patients with ribosomopathies. Together, our findings identify HNRNPK as a master regulator of ribosome biogenesis and nucleolar homeostasis through p53, providing what we believe to be a new perspective on the orchestration of nucleolar integrity, ribosome function and cellular senescence.
Authors
- Rosa García-Martín
- Eduardo J. Caleiras (ORCID: https://orcid.org/0000-0001-8768-3630)
- Marta Isasa (ORCID: https://orcid.org/0009-0005-6865-9500)
- Marisa J.L. Aitken (ORCID: https://orcid.org/0000-0002-7937-531X)
- Pedro Aguilar-Garrido (ORCID: https://orcid.org/0000-0002-4909-8307)
- Oscar Benitez
- Pilar Ximénez‐Embún (ORCID: https://orcid.org/0000-0002-2582-9443)
- Vanesa Lafarga (ORCID: https://orcid.org/0000-0001-8336-1124)
- Joaquín Martínez‐López (ORCID: https://orcid.org/0000-0001-7908-0063)
- Gadea Mata (ORCID: https://orcid.org/0000-0002-5567-8463)
- Prerna Malaney (ORCID: https://orcid.org/0000-0002-4667-4823)
- Miguel Lafarga (ORCID: https://orcid.org/0000-0003-3402-1152)
- Andrés Penagos‐Puig (ORCID: https://orcid.org/0009-0005-1033-1609)
- Miguel Ángel Navarro-Aguadero (ORCID: https://orcid.org/0000-0002-8326-8517)
- Josune Zubicaray (ORCID: https://orcid.org/0000-0003-4115-9598)
- María Hernández‐Sánchez (ORCID: https://orcid.org/0000-0001-9968-2782)
- Jesús Gómez (ORCID: https://orcid.org/0000-0002-8567-8907)
- Alvaro Otero-Sobrino
- Raúl Torres (ORCID: https://orcid.org/0000-0001-9606-0398)
- Julián Sevilla (ORCID: https://orcid.org/0000-0002-6852-1860)
- Diego Megı́as (ORCID: https://orcid.org/0000-0003-0755-0518)
- Manuel Pérez‐Martínez (ORCID: https://orcid.org/0000-0001-8839-6895)
- Sandra Rodríguez (ORCID: https://orcid.org/0000-0001-7221-3636)
- María Velasco‐Estevez (ORCID: https://orcid.org/0000-0002-2886-122X)
- Osvaldo Graña‐Castro (ORCID: https://orcid.org/0000-0003-1615-4242)
- Marta Ibáñez-Navarro (ORCID: https://orcid.org/0000-0002-5711-4768)
- Alejandra Ortiz-Ruiz (ORCID: https://orcid.org/0000-0003-4059-8839)
- Enrique Revilla (ORCID: https://orcid.org/0000-0001-5394-5401)
- Oleksandra Sirozh (ORCID: https://orcid.org/0000-0003-0696-724X)
- Miguel Gallardo (ORCID: https://orcid.org/0000-0002-3699-9130)
- Sean M. Post (ORCID: https://orcid.org/0000-0001-9225-200X)
- Xiaorui Zhang (ORCID: https://orcid.org/0000-0002-7030-6529)
- Orlando Domı́nguez (ORCID: https://orcid.org/0000-0002-7016-6490)
- Ashley Rodriguez
- Daniel Azorín
- Miguel Ángel Marugal
Institutions
- Dartmouth College (US)
- Universidad San Pablo CEU (ES)
- Universidad Complutense de Madrid (ES)
- Universidad de Cantabria (ES)
- The University of Texas MD Anderson Cancer Center (US)
- Research Institute Hospital 12 de Octubre (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Spanish National Cancer Research Centre (ES)
- Abterra Biosciences (United States) (US)
- Hospital Universitario 12 De Octubre (ES)
- Hospital Infantil Universitario Niño Jesús (ES)
- Instituto de Investigación Marqués de Valdecilla (ES)
- Centro de Investigación Biomédica en Red (ES)
- Dartmouth Psychiatric Research Center (US)
- Centro de Investigación del Cáncer (ES)
- Centro Nacional de Análisis Genómico (ES)
- Genomics (United Kingdom) (GB)
- HistoGenetics (United States) (US)
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (ES)
- Athens State University (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-05-08
- DOI
- https://doi.org/10.1172/jci183697
- Citations
- 2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- European Commission
- Fundación Científica Asociación Española Contra el Cáncer
- Fundación Española de Hematología y Hemoterapia
- CRIS Cancer Foundation
- Instituto de Salud Carlos III
- European Regional Development Fund
- HORIZON EUROPE Marie Sklodowska-Curie Actions