Targeting Cancer-Specific Mutations with RNA-Triggered Chromatin Shredding

  • Nature. 2026 Jun 8. doi: 10.1038/s41586-026-10738-7.
Jingkun Zeng  1  2  3  4 ,  Zhiyuan Cheng  #  1  2 ,  Huadong Chen  #  5 ,  Zhaojun Wang  #  1  2 ,  Jared Thompson  6 ,  Kadin T Crosby  7 ,  Hesong Han  3 ,  Arushi Singhal  1  2 ,  Wayne Ngo  1  2  3  4 ,  Chenglong Xia  3 ,  Daniel Rosas-Rivera  1  2 ,  Zeyuan Zhang  3  4 ,  Min Hyung Kang  3 ,  Ying Mao  5 ,  Morgan E Diolaiti  5 ,  Giselle C Lee  8 ,  John F X Diffley  8 ,  Yixuan Song  8 ,  Longhui Qiu  9 ,  Nathan M Krah  6  10 ,  Niren Murthy  3  11 ,  Ryan N Jackson  7 ,  Yang Liu  6 ,  Alan Ashworth  5 ,  Jennifer A Doudna  12  13  14  15  16  17  18  19  20
Affiliations
  • 1. Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA.
  • 2. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
  • 3. Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
  • 4. California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
  • 5. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
  • 6. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • 7. Department of Chemistry and Biochemistry, Utah State University, Logan, UT, USA.
  • 8. The Francis Crick Institute, London, UK.
  • 9. Department of Medicine, UCSF, San Francisco, California, USA.
  • 10. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
  • 11. Department of Bioengineering, University of California Berkeley, Berkeley, CA, USA.
  • 12. Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA. [email protected].
  • 13. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. [email protected].
  • 14. Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 15. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 16. Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 17. Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. [email protected].
  • 18. California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 19. Li Ka Shing Center for Genomic Engineering, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 20. Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • # Contributed equally.
PMID: 42259916 DOI: 10.1038/s41586-026-10738-7
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 limits cell growth by inducing trans shredding of chromatin, triggering DNA damage responses and cell death. Unlike existing methods, RNA-guided Cas12a2 senses cellular RNA signatures, enabling precise targeting of undruggable mutations. Transcript-activated chromatin shredding provides a new approach to precision disease treatments for undruggable targets.

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