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A multiparametric anti-aging CRISPR screen uncovers a role for BAF in protein synthesis regulation

Author

Listed:
  • Sophia Y. Breusegem

    (Hills Road
    Tennis Court Road)

  • Jack Houghton

    (Hills Road
    South Kensington)

  • Raquel Romero-Bueno

    (Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Junta de Andalucía)

  • Adrián Fragoso-Luna

    (Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Junta de Andalucía)

  • Katherine A. Kentistou

    (Institute of Metabolic Science)

  • Ken K. Ong

    (Institute of Metabolic Science)

  • Anne F. J. Janssen

    (Hills Road
    Heyendaalseweg 135)

  • Nicholas A. Bright

    (Hills Road)

  • Christian G. Riedel

    (141 57)

  • John R. B. Perry

    (Institute of Metabolic Science
    University of Cambridge School of Clinical Medicine)

  • Peter Askjaer

    (Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Junta de Andalucía)

  • Delphine Larrieu

    (Hills Road
    Cambridge Institute of Science)

Abstract

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.

Suggested Citation

  • Sophia Y. Breusegem & Jack Houghton & Raquel Romero-Bueno & Adrián Fragoso-Luna & Katherine A. Kentistou & Ken K. Ong & Anne F. J. Janssen & Nicholas A. Bright & Christian G. Riedel & John R. B. Perry, 2025. "A multiparametric anti-aging CRISPR screen uncovers a role for BAF in protein synthesis regulation," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56916-5
    DOI: 10.1038/s41467-025-56916-5
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    References listed on IDEAS

    as
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