New Results
, Zhiyuan Cheng, Huadong Chen, Jared Thompson, Kadin T. Crosby, Hesong Han, Wayne Ngo, Chenglong Xia, Daniel Rosas-Rivera, Min Hyung Kang, Ying Mao, Giselle Lee, John F. X. Diffley, Yixuan Song, Longhui Qiu, Nathan M. Krah, Niren Murthy, Ryan N. Jackson, Yang Liu, Alan Ashworth, View ORCID ProfileJennifer A. Doudna
doi: https://doi.org/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.
Competing Interest Statement
The Regents of the University of California have patents issued and pending for CRISPR technologies on which J.A.D. and J.Z. are inventors. J.A.D. is a cofounder of Aurora, Azalea Therapeutics, Caribou Biosciences, Editas Medicine, Scribe Therapeutics and Mammoth Biosciences. J.A.D. is a scientific advisory board member at BEVC Management, Caribou Biosciences, Scribe Therapeutics, Isomorphic Labs, The Column Group and Inari. She also is an advisor for Aditum Bio. J.A.D. is Chief Science Advisor to Sixth Street, and a Director at Johnson & Johnson, Altos and Tempus. A.A. is a co-founder of Azkarra Therapeutics, Kytarro, Ovibio Corporation, Tango Therapeutics and Tiller Tx; a member of the board of Cambridge Science Corporation, Cytomx, and Ovibio; a member of the scientific advisory board of Ambagon, Bluestar/Clearnote Health, Circle, GLAdiator, HAP10, Interdict Bio Inc., Earli, ORIC, Phoenix Molecular Designs, Trial Library, Yingli/280Bio; a consultant for Next RNA, Novartis, ProLynx; and holds patents on the use of PARP inhibitors held jointly with AstraZeneca from which he has benefited financially (and may do so in the future). N.M. is a cofounder of Genedit, Microbial Medical and Opus Biosciences. No other authors declare any conflicts of interest.
Copyright
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