Selective Elimination of TP53 Mutant Cells by Transcript-Activated Chromatin Shredding

  • bioRxiv. 2026 May 9:2026.05.08.723607. doi: 10.64898/2026.05.08.723607.
Jingkun Zeng  1  2  3 ,  Zhiyuan Cheng  1  2 ,  Huadong Chen  4 ,  Jared Thompson  5 ,  Kadin T Crosby  6 ,  Hesong Han  3 ,  Wayne Ngo  1  2  3 ,  Chenglong Xia  3 ,  Daniel Rosas-Rivera  1  2 ,  Min Hyung Kang  3 ,  Ying Mao  4 ,  Giselle Lee  7 ,  John F X Diffley  7 ,  Yixuan Song  7 ,  Longhui Qiu  8 ,  Nathan M Krah  5  9 ,  Niren Murthy  3  10 ,  Ryan N Jackson  6 ,  Yang Liu  5 ,  Alan Ashworth  4 ,  Jennifer A Doudna  1  2  3  11  12  13  14  15  16
Affiliations
  • 1. Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA, 94158.
  • 2. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA, 94158.
  • 3. Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA, 94720.
  • 4. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
  • 5. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • 6. Department of Chemistry and Biochemistry, Utah State University, Logan, UT, USA.
  • 7. The Francis Crick Institute, London, UK.
  • 8. Department of Medicine, UCSF, San Francisco, California, USA.
  • 9. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
  • 10. Department of Bioengineering, University of California Berkeley, Berkeley, CA, USA, 94720.
  • 11. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA, 94720.
  • 12. Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA USA, 94720.
  • 13. Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA, 94720.
  • 14. California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA, 94720.
  • 15. Li Ka Shing Center for Genomic Engineering, University of California, Berkeley, Berkeley, CA, USA, 94720.
  • 16. Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA, 94720.
PMID: 42146678 DOI: 10.64898/2026.05.08.723607
Abstract

Genetic mutations that drive Cancer often occur in tumor suppressor proteins, including the p53 transcription factor which is altered in ~40-50% of cases1,2. However, current therapies fail to target most such mutations because the mutant proteins typically lack defined drug-binding pockets, and restoring the endogenous function has proven challenging. Here, we programmed CRISPR-Cas12a2, an RNA-guided nuclease with trans-nucleolytic cleavage activities3,4, to selectively kill Cancer cells by targeting cancer-specific transcripts. This approach eliminates cells by inducing trans chromatin cleavage, triggering DNA damage and cell death. Unlike existing methods, RNA-guided Cas12a2 senses cellular RNA signatures to shred chromatin, enabling precise targeting of undruggable mutations. Transcript-activated chromatin shredding provides an innovative paradigm to develop precision disease treatments for undruggable targets.

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