Targeting cancer-specific mutations with RNA-triggered chromatin shredding

Authors list

Jingkun Zeng Zhiyuan Cheng Huadong Chen Zhaojun Wang Jared Thompson Kadin T Crosby Hesong Han Arushi Singhal Wayne Ngo Chenglong Xia Daniel Rosas-Rivera Zeyuan Zhang Min Hyung Kang Ying Mao Morgan E Diolaiti Giselle Lee John Diffley Yixuan Song Longhui Qiu Nathan M Krah Niren Murthy Ryan N Jackson Yang Liu Alan Ashworth Jennifer A Doudna
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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.

Journal details

Journal Nature
Volume 656
Issue number 8126
Pages 199-206
Available online
Publication date

Full text links

Publisher website (DOI) 10.1038/s41586-026-10738-7
Europe PubMed Central 42259916
Pubmed 42259916

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Publishing history

The publication was previously a preprint. View preprint