Zeng, J.; Cheng, Z.; Chen, H.; Thompson, J.; Crosby, K. T.; Hang, H.; Ngo, W.; Xia, C.; Rosas-Rivera, D.; Kang, M. H.; Mao, Y.; Lee, G.; Diffley, J. F. X.; Song, Y.; Qiu, L.; Krah, N. M.; Murthy, N.; Jackson, R. N.; Liu, Y.; Ashworth, A.; Doudna, J. A.

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.