2. Academic Validation
  3. Targeting Cancer-Specific Mutations with RNA-Triggered Chromatin Shredding

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

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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