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Updated: Jun 10, 2026

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
07:23

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells

Published on: May 30, 2025

Targeting cancer-specific mutations with RNA-triggered chromatin shredding

Jingkun Zeng1,2,3,4, Zhiyuan Cheng1,2,5, Huadong Chen6

  • 1Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA.

Nature
|June 8, 2026
PubMed

Insights

Researchers developed a new CRISPR-Cas12a2 system to target cancer-specific RNA, leading to chromatin shredding and cancer cell death. This approach offers a novel strategy for treating cancers with undruggable mutations.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Genetic mutations in tumor suppressor proteins like p53 are common drivers of cancer.
  • Current therapies struggle to target these mutations due to a lack of drug-binding pockets and challenges in restoring protein function.

Purpose of the Study:

  • To develop a novel therapeutic strategy for targeting cancer-specific transcripts.
  • To utilize CRISPR-Cas12a2 for selective cancer cell killing via RNA-guided chromatin shredding.

Main Methods:

  • Programmed CRISPR-Cas12a2, an RNA-guided nuclease, to target cancer-specific transcripts.
  • Induced trans-nucleolytic cleavage of target RNA, leading to chromatin shredding.
  • Triggered DNA damage responses and cell death in cancer cells.

Main Results:

  • Demonstrated selective killing of cancer cells by targeting cancer-specific RNA signatures.
  • Showcased transcript-activated chromatin shredding as a mechanism for cancer cell death.
  • Validated the potential of RNA-guided Cas12a2 for targeting previously undruggable mutations.

Conclusions:

  • CRISPR-Cas12a2 offers a precise method for targeting cancer-specific transcripts.
  • Transcript-activated chromatin shredding presents a new therapeutic avenue for cancers with undruggable targets.
  • This approach enhances precision medicine by addressing genetic mutations resistant to conventional therapies.

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