While CRISPR-Cas9 excels at precise cuts, CRISPR-Cas3 erases long DNA sections, opening doors to curing persistent viral infections and understanding non-coding DNA.
For years, the story of CRISPR gene editing has been dominated by a single star: the CRISPR-Cas9 system, often called "genetic scissors." But while Cas9 excels at making precise cuts, a powerful new tool is emerging from the shadows. Meet CRISPR-Cas3, the genome's "bulldozer," a system that doesn't just snip DNA—it erases long sections of it1 .
This technology is opening doors to curing persistent viral infections and understanding the vast, mysterious regions of our genome that control our biology.
Use a complex of multiple proteins to target and cut foreign DNA. Includes Types I, III, and IV6 .
Use a single, multi-domain protein for targeting and cutting DNA. Includes Cas9, Cas12, and Cas13.
CRISPR-Cas3 is the signature effector of the most widespread type of CRISPR systems in nature: Type I, a Class 1 system8 . Its operation is a two-step process:
A large, multi-protein complex called Cascade acts as a seeker. It uses a guide RNA to scan DNA and latches onto the target site.
Cascade recruits Cas3, which unwinds the DNA and acts like a shredder, erasing long stretches—up to 100 kilobases4 .
| Feature | CRISPR-Cas3 (The Bulldozer) | CRISPR-Cas9 (The Scissors) |
|---|---|---|
| CRISPR Class | Class 1 (multi-protein complex) | Class 2 (single effector protein) |
| Primary Action | Unwinds and degrades long segments of DNA from a target site | Makes a precise double-strand break in the DNA |
| Editing Outcome | Large-scale deletions | Small insertions, deletions, or replacements |
| Best Suited For | Erasing large genetic elements, screening non-coding DNA, targeting viral genomes | Gene knockout, precise point mutations, gene insertion |
For years, the potential of CRISPR-Cas3 was confined to test tubes. A pivotal breakthrough came in 2019 when a collaborative team from Cornell University and the University of Michigan achieved what was once thought to be a significant hurdle: they successfully demonstrated CRISPR-Cas3 genome editing in human cells4 .
They introduced the genetic instructions for the entire Cascade complex and the Cas3 protein into human embryonic stem cells and another cell line called HAP1.
The system was programmed to seek out a specific, pre-determined sequence within the human genome.
Once the Cascade complex located and bound to its target, it recruited Cas3. The team then analyzed the cells' DNA to see if the promised large-scale deletion occurred.
The results, published in the journal Molecular Cell, were a resounding success. The team demonstrated that CRISPR-Cas3 could efficiently erase targeted sequences of DNA. Crucially, they confirmed the deletions were extensive, reaching up to 100 kilobases in length4 .
This experiment was not just a technical showcase. It revealed the immense therapeutic potential of Cas3 for targeting viruses very specifically and erasing them efficiently, suggesting a potential cure for persistent viral infections like herpes simplex, Epstein-Barr, and hepatitis B4 .
Shredding the integrated viral DNA genome from infected human cells for a one-time, curative treatment for infections like herpes and hepatitis B.
Deleting large sections of non-coding DNA to see what function is lost, unlocking the secrets of the 98% of our genome that doesn't code for proteins.
Removing large oncogenic gene sequences or regulatory elements to study and potentially disable complex genetic drivers of cancer.
While Cas3 is excellent at making large deletions, controlling the exact boundaries of that deletion remains difficult4 . For therapeutic use, scientists must be able to predict the deletion size with high accuracy to avoid unintended genetic damage.
Despite current hurdles, the future is bright. The ability to erase large sections of DNA provides a unique power to explore the "dark matter" of the genome.
CRISPR-Cas3 is more than just a new set of genetic tools; it represents a fundamental shift in capability. It moves us beyond editing genes letter-by-letter to rewriting entire paragraphs of our genetic code, offering a powerful new strategy to confront diseases that have long been out of reach.
This article is based on scientific reports and studies. The technologies discussed are primarily in the research phase and are not yet widely available as clinical treatments.