AI Article Synopsis
- 6mer seed toxicity, a new mechanism for inducing cell death, targets cancer cells by eliminating survival genes via death induced by survival gene elimination (DISE).
- Researchers screened thousands of 6mer seeds and found that G-rich sequences, particularly GGGGGC, are the most toxic to human cancer cells, affecting mouse cells less significantly.
- The mechanism involves targeting specific gene sequences in the 3' UTR of survival genes with a toxic siRNA (siGGGGGC), suggesting the potential use of artificial miRNAs as new cancer therapies.
Article Abstract
6mer seed toxicity is a novel cell death mechanism that kills cancer cells by triggering death induced by survival gene elimination (DISE). It is based on si- or shRNAs with a specific G-rich nucleotide composition in position 2-7 of their guide strand. An arrayed screen of 4096 6mer seeds on two human and two mouse cell lines identified G-rich 6mers as the most toxic seeds. We have now tested two additional cell lines, one human and one mouse, identifying the GGGGGC consensus as the most toxic average 6mer seed for human cancer cells while slightly less significant for mouse cancer cells. RNA Seq and bioinformatics analyses suggested that an siRNA containing the GGGGGC seed (siGGGGGC) is toxic to cancer cells by targeting GCCCCC seed matches located predominantly in the 3' UTR of a set of genes critical for cell survival. We have identified several genes targeted by this seed and demonstrate direct and specific targeting of GCCCCC seed matches, which is attenuated upon mutation of the GCCCCC seed matches in these 3' UTRs. Our data show that siGGGGGC kills cancer cells through its miRNA-like activity and points at artificial miRNAs, si- or shRNAs containing this seed as a potential new cancer therapeutics.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948288 | PMC |
| http://dx.doi.org/10.1038/s41598-022-09051-w | DOI Listing |
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