Ribo-Tweezer: Rapid removal of ribosomal proteins reveals additional layers of post-transcriptional gene regulation

  • Mol Cell. 2026 Jul 2;86(13):2635-2651.e9. doi: 10.1016/j.molcel.2026.04.023.
Yuxiang Chen  1 ,  Ching Pin Cheng  1 ,  Kitra Cates  1 ,  Georgi K Marinov  1 ,  Travis C Lantz  2 ,  Haojun Yang  3 ,  Isabelle Liu  3 ,  Naomi R Genuth  1 ,  Christina Andronescu  4 ,  Victoria Hung  1 ,  Abel Bermudez  5 ,  Daphna Rothschild  1 ,  Joseph Georgeson  6 ,  Sonia Bustos Barocio  1 ,  Anshul Kundaje  7 ,  Sharon Pitteri  5 ,  Davide Ruggero  3 ,  Maria Barna  8
Affiliations
  • 1. Department of Genetics, Stanford School of Medicine, Stanford, CA, USA.
  • 2. Department of Genetics, Stanford School of Medicine, Stanford, CA, USA; Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford, CA, USA.
  • 3. Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA, USA; School of Medicine and Department of Urology, UCSF, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, CA, USA.
  • 4. Department of Genetics, Stanford School of Medicine, Stanford, CA, USA; Department of Human Biology, Stanford University, Stanford, CA, USA.
  • 5. Department of Radiology, Stanford School of Medicine, Stanford, CA, USA.
  • 6. Department of Genetics, Stanford School of Medicine, Stanford, CA, USA; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
  • 7. Department of Genetics, Stanford School of Medicine, Stanford, CA, USA; Department of Computer Science, Stanford University, Stanford, CA, USA.
  • 8. Department of Genetics, Stanford School of Medicine, Stanford, CA, USA. Electronic address: [email protected].
PMID: 42167236 DOI: 10.1016/j.molcel.2026.04.023
Abstract

The ribosome is a ribozyme, but it also acts as a dynamic regulator of gene expression. Although ribosomal protein (RP) composition varies, dissecting the functional contributions of individual RPs beyond their housekeeping roles is challenging because of the lack of tools for manipulation in situ. Here, we developed Ribo-Tweezer, a degron-based system directly tethered to mature ribosomes that enables rapid, reversible, and selective depletion of specific RPs. Using Ribo-Tweezer in mouse embryonic stem cells (mESC), we find a previously uncharacterized role for RACK1 in stem cell fate control via translational regulation of zinc-finger transcriptional networks and long interspersed nuclear element-1 (LINE1) expression. This translation-transcription coupling provides a mechanism by which translation control is further amplified in gene regulation. Distinct translational programs induced by RPLP0 and RPLP1 depletion further demonstrate RP-specific regulatory functions in translation. Together, these findings establish Ribo-Tweezer as a powerful platform that has illuminated selective functions for RPs in gene regulation, which gives biological meaning to ribosome heterogeneity.

Keywords
LINE-1; P-stalk; Poly(A/U) leader; RACK1; mESC differentiation; ribosome; ribosome heterogeneity; translation control.
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