A multiparametric anti-aging CRISPR screen uncovers a role for BAF in protein synthesis regulation
Progeria syndromes are very rare, incurable premature aging conditions recapitulating most aging features. Here, we report a whole genome, multiparametric CRISPR screen, identifying 43 genes that can rescue multiple cellular phenotypes associated with progeria. We implement the screen in fibroblasts from Néstor-Guillermo Progeria Syndrome male patients, carrying a homozygous A12T mutation in BAF. The hits are enriched for genes involved in protein synthesis, protein and RNA transport and osteoclast formation and are validated in a whole-organism Caenorhabditis elegans model. We further confirm that BAF A12T can disrupt protein synthesis rate and fidelity, which could contribute to premature aging in patients. This work highlights the power of multiparametric genome-wide suppressor screens to identify genes enhancing cellular resilience in premature aging and provide insights into the biology underlying progeria-associated cellular dysfunction.
Authors
- Delphine Larrieu (ORCID: https://orcid.org/0000-0002-2335-9361)
- Ken K. Ong (ORCID: https://orcid.org/0000-0003-4689-7530)
- Anne F. J. Janssen (ORCID: https://orcid.org/0000-0003-1227-2006)
- Nicholas A. Bright (ORCID: https://orcid.org/0000-0002-2791-6727)
- John R. B. Perry (ORCID: https://orcid.org/0000-0001-6483-3771)
- Adrián Fragoso-Luna (ORCID: https://orcid.org/0000-0003-0325-7293)
- Christian G. Riedel (ORCID: https://orcid.org/0000-0002-3689-8022)
- Katherine A. Kentistou (ORCID: https://orcid.org/0000-0002-5816-664X)
- Raquel Romero-Bueno (ORCID: https://orcid.org/0000-0001-7454-2759)
- Peter Askjaer (ORCID: https://orcid.org/0000-0003-3192-4428)
- Jack W. Houghton (ORCID: https://orcid.org/0000-0002-2971-0271)
- Sophia Y. Breusegem
Institutions
- New England Biolabs (United States) (US)
- Consejo Superior de Investigaciones Científicas (ES)
- Radboud University Nijmegen (NL)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Karolinska Institutet (SE)
- Centro Andaluz de Biología del Desarrollo (ES)
- Wellcome/MRC Institute of Metabolic Science (GB)
- MRC Epidemiology Unit (GB)
- Imperial College London (GB)
- Junta de Andalucía (ES)
- Universidad Pablo de Olavide (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-16
- DOI
- https://doi.org/10.1038/s41467-025-56916-5
- Citations
- 1
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Wellcome Trust
- Cancerfonden
- Novo Nordisk
- Vetenskapsrådet
- Novo Nordisk Fonden
- Medical Research Council
- Cambridge Institute for Medical Research, University of Cambridge
- Agencia Estatal de Investigación