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Innovative chromatin shredding technique shown to selectively destroy cancer cells carrying a mutation found in nearly half of all cancer cases
The job of a tumor suppressor A string of amino acids folded into a three-dimensional structure. Proteins are each specialized to perform a specific role to help cells grow, divide, and function. One of the four macromolecules that make up all living things (protein, lipids, carbohydrates, and nucleic acids).
” href=”https://innovativegenomics.org/glossary/protein/” data-mobile-support=”0″ data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>protein is right in the name: stopping us from getting cancer at the cellular level. But when they’re not working properly, the cell is left with limited defenses.
In a new paper published today in the journal Nature titled “Targeting Cancer-Specific Mutations with RNA-Triggered Chromatin Shredding,“ researchers at the Innovative The study of the genome, all the DNA from a given organism. Involves a genome’s DNA sequence, organization and control of genes, molecules that interact with DNA, and how these different components affect the growth and function of cells.
” href=”https://innovativegenomics.org/glossary/genomics/” data-mobile-support=”0″ data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>Genomics Institute (IGI) at UC Berkeley, UC San Francisco, and Gladstone Institutes, along with collaborators at University of Utah and Utah State University, report that a creative new CRISPR-based approach can selectively destroy cells carrying a A change from one genetic letter (nucleotide) to another. Variation in DNA sequence gives rise to the incredible diversity of species in the world, and even occurs between different organisms of the same species. While some mutations have no consequence at all, certain mutations can directly cause disease. Mutations may be caused by DNA-damaging agents such as UV light or may arise from errors that occur when DNA is copied by cellular enzymes. They can also be made deliberately via genome engineering methods.
” href=”https://innovativegenomics.org/glossary/mutation/” data-mobile-support=”0″ data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>mutation in a tumor suppressor found in nearly half of all cancers and up to 70–90% of cases of some of the most difficult-to-treat cancers, including ovarian, pancreatic, and non-small cell lung cancer.
“Not only can this approach target the ‘undruggable’ cancers that we know, we can also easily and quickly adapt this to new mutations,” says IGI Founder Jennifer Doudna, a co-author on the paper. “This is an exciting development for cancer therapies, and potentially for other applications as well.”
A common mutation behind many cancers
First author Jingkun Zeng, a postdoctoral researcher in Doudna’s lab, did his Ph.D. research at the Francis Crick Institute on cancer evolution and was looking to find new ways to target the so-called “undruggable” cancer mutations and thought tumor suppressors might hold the key.
“If you look at all the cancer drugs right now, they’re mostly inhibitors. They suppress an overactive cancer gene,” says Zeng. “But for tumor suppressors, it’s the opposite. When they develop a mutation, they lose their function. They can no longer suppress tumor formation.”
The role of a specific protein called p53 as a tumor suppressor has been known since the late 1980s. Mutations in this gene help cancers grow uninhibited and are common across many cancer types. Because of this, and because it is often an early mutation that drives later mutations in the cancer-causing <p><span style=”font-weight: 400;”>A protein complex derived from the CRISPR-Cas bacterial immune system that has been co-opted for genome engineering. Cascade is composed of multiple Cas proteins. The complex uses a crRNA as a guide to find a complementary DNA sequence. Once the target DNA is identified, Cascade recruits a separate nuclease-helicase called Cas3 to move along the DNA, cutting as it goes. In CRISPR immunity, cutting phage DNA prevents phages from replicating and it from destroying the host cell. When used for genetic engineering, this approach can be used to delete thousands of base pairs around the target site.</span></p>
” href=”https://innovativegenomics.org/glossary/cascade/” data-mobile-support=”0″ data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>cascade, researchers have long considered it one of the premium targets for cancer therapy. Despite the promise, not a single p53-targeting drug has made it to the market. Not only do tumor suppressor proteins lack “druggable pockets,” the areas on the molecule where small molecule drugs can fit like a key in a lock, it’s not clear how drugging mutated p53 protein could help it do its job.
Going back to CRISPR basics
Zeng, inspired by reading a paper from the Doudna Lab on using CRISPR to shred repetitive sequences in brain tumors, thought there might be an alternative to reactivating broken tumor suppressors: finding cells with cancer-specific mutations and eliminating them entirely.
“People generally, and especially in the gene editing field, want to fix genes or knock out genes,” says Zeng. “But what I wanted to do here is completely different. I wanted to destroy abnormal cells, precisely and safely.”
This approach takes CRISPR back to its roots; in nature CRISPR systems are destroyers not fixers. They defend microbes against infections by cutting the genetic material of invading viruses to prevent damage and replication. Instead of reactivating a broken p53 protein, the research team reasoned that they could harness CRISPR’s natural ability to find cells with specific mutations and use its cutting ability to selectively destroy those cells.
The research team engineered a CRISPR system called CRISPR-Cas12a2 to look for the specific RNA transcript produced only by cells with the mutated cancer gene. In An abundant type of microbe. These single-celled organisms are invisible to the naked eye, don’t have a nucleus, and can have many shapes. They’re found in all types of environments, from Arctic soil to inside the human body. Most bacteria are not harmful to human health, but certain pathogenic bacteria can cause illness.
” href=”https://innovativegenomics.org/glossary/bacteria/” data-mobile-support=”0″ data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>bacteria, this CRISPR acts as a suicide pill, intentionally killing a cell that has been infected by a virus to prevent its spread. In the newly engineered version, once the system detects a cancer signature within a cell, the Cas12a2 enzyme activates and initiates “chromatin shredding,” slicing up all the genetic material inside that specific cell. This widespread genetic demolition triggers cell death, destroying mutated cells while leaving healthy cells completely untouched.
“This new approach reimagines how CRISPR can be used as a precision tool to find and eliminate cancer cells across a variety of cancer types. It may open up many new previously undruggable targets for cancer therapy,” says co-author Alan Ashworth, President of the Helen Diller Family Comprehensive Cancer Center at UCSF and co-director of the CRISPR Cures for Cancer initiative.
For this approach to be useful in real-world situations, however, it has to be precise and not cause harm to healthy cells. To test the accuracy of this method, the team introduced the CRISPR-Cas12a2 system into mammalian cell cultures containing both healthy and cancerous cells. The system successfully distinguished between the two, initiating chromatin shredding and cell death only when the specific mutant RNA was present. Cells carrying the healthy, wild-type version were left almost entirely unharmed.
“Those two cell lines, they just differed by one One of the basic chemical units strung together to make DNA or RNA. Consists of a base, a sugar, and a phosphate group. The phosphates can link with sugars to form a string called the DNA/RNA backbone, while the bases can bind to their complementary partners to form base pairs.
” href=”https://innovativegenomics.org/glossary/nucleotide/” data-mobile-support=”0″ data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>nucleotide change,” says Zeng. “When people treat cancer with chemotherapy or radiotherapy, that’s essentially killing all the dividing cells in the body, including healthy cells. With this technology, it’s much, much more precise.”
A slicer for all occasions
While the team is excited about the results with p53, Zeng thinks that the main advantage of this technology is that it is programmable, just like more traditional types of CRISPR gene editing.
“In cancer, when there’s a new mutation, we can now easily make a new guide RNA to find the new mutation and test if it’s effective. This is much faster than making a small molecule drug or antibody therapy,” says Zeng.
Zeng is now thinking about the next steps with this approach and how to overcome some of its limitations. Much like other CRISPR therapies, delivery is a critical challenge, i.e., getting the large genome-cutting enzyme to all the targeted cells efficiently. He also thinks that combination therapies may prove useful for some cancers in the future.
Read more: Targeting Cancer-Specific Mutations with RNA-Triggered Chromatin Shredding. Zeng J, et al. (2026), Nature DOI: 10.1038/s41586-026-10738-7. https://www.nature.com/articles/s41586-026-10738-7
Top image by Issah, Adobe Stock
By Andy Murdock
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