CRISPR fingers new cancer targets among mysterious genes shared by rodents and people

Some segments of genes shared between human, mouse and rat genomes could serve as new targets for developing treatments against cancer, scientists at Fred Hutchison have found. (Kim Carney/Fred Hutch News Service)

In 2004, scientists found 481 segments of DNA that are shared between human, rat and mouse genomes. These ultra-conserved bits must be essential if they could survive millions of years of evolution and remain unchanged, they suspected. But how?

Researchers at Fred Hutchison Cancer Research Center have used the CRISPR-Cas9 gene-editing tool to demonstrate that some of those DNA elements are key for cell growth and suppressing tumors. Therefore, targeting them may represent a new approach for developing anti-cancer treatments, they argue.

The research, published in the journal Nature Genetics, is the “first study finding large-scale importance of these highly conserved [DNA] elements,” senior author Rob Bradley said in a statement.

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Bradley and colleagues focused their research on parts of DNA called poison exons. Cells can sometimes skip exons to make RNA during the protein-production step known as RNA splicing. But poison exons can act as a “kill switch” to put an end to protein production. It’s usually a beneficial process that helps avoid the production of unwanted proteins.

Previous studies have found wide overlaps between ultra-conserved DNA pieces and poison exons, but efforts to understand exactly what that signifies have been largely fruitless. 

Rather than focusing on one specific ultra-conserved DNA element, first author James Thomas, a postdoc fellow in Bradly’s lab, designed a CRISPR-based tool that allowed the researchers to remove and examine hundreds of poison exons at the same time.

The researchers compared 465 highly conserved poison exons to 91 others that are not shared between species. They found that many poison exons are essential for the growth of cells cultured in lab dishes, as removing them led to cell death.

To validate the findings, the team tested mice with lung cancer xenografts. They observed that some poison exons helped promote cell growth, but a subset had anti-tumor effects. Many of the anti-tumor poison exons were within the genes regulating RNA splicing factors, which are produced at increased levels in cancer.

“These data suggest that many RNA splicing factors are proto-oncoproteins whose pro-tumorigenic effects are constrained by poison exons,” the researchers wrote in the study.

By examining poison exons in lung cancer patients, the scientists confirmed that their tumor-suppressing capacity was clinically relevant, as low inclusion of tumor-fighting poison exons was linked to significantly worse survival rates, they reported.

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Drugs that target RNA mis-splicing are in use now to treat some diseases. Biogen’s antisense oligonucleotide Spinraza (nusinersen), for example, treats spinal muscular atrophy by correcting SMN2 exon 7 splicing to compensate for the loss of SMN1.

The Fred Hutch team figured the new findings could open up the possibility of targeting ultra-conserved poison exons with drug treatments. “Once you find a target, it's easy to build upon the previous technology that exists for therapeutics,” Thomas said in the statement.

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