bioRxiv : the preprint server for biology · 2026
Selective Elimination of TP53 Mutant Cells by Transcript-Activated Chromatin Shredding.
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Zeng Jingkun, Cheng Zhiyuan, Chen Huadong, Thompson Jared, Crosby Kadin T, Han Hesong, Ngo Wayne, Xia Chenglong, Rosas-Rivera Daniel, Kang Min Hyung, Mao Ying, Lee Giselle, Diffley John F X, Song Yixuan, Qiu Longhui, Krah Nathan M, Murthy Niren, Jackson Ryan N, Liu Yang, Ashworth Alan, Doudna Jennifer A
Аннотация
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.