Targeting Cancer-Specific Mutations with RNA-Triggered Chromatin Shredding.
basic_science · Level V
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- Record sourced from PubMed, PMID 42259916.
- Also identified by DOI 10.1038/s41586-026-10738-7.
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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 cases<sup>1,2</sup>. 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 activities<sup>3,4</sup>, 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.