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September 2, 2024

Unveiling the mechanism of action of the anticancer agent DMDA-PatA

An international collaborative research group consisting of the RIKEN Cluster for Pioneering Research, the RIKEN CSRS, the RIKEN Center for Biosystems Dynamics Research, and Osaka University Graduate School has elucidated the mechanism of action of the small molecule compound desmethyl, desamino pateamine A (DMDA-PatA), which exhibits anti-cancer activity. DMDA-PatA has been reported to show high toxicity to certain cancer cells while having low toxicity to normal cells, suggesting that this cell-specific toxicity holds potential for avoiding the severe side effects of chemotherapy. Until now, DMDA-PatA was thought to inhibit the translation process in gene expression, but how it suppressed translation remained unclear.

In this study, the research group discovered that DMDA-PatA functions as steric hindrance, obstructing the progression of scanning ribosomes searching for the translation initiation site by tightly binding RNA-binding proteins eIF4A and DDX3 to specific sequences (GNG motifs: G represents a guanine base, N represents any base) on messenger RNA (mRNA). This selective inhibition of mRNA translation sheds light on how DMDA-PatA exerts its effects. Furthermore, the findings from this research will be valuable for investigating which cancer cells DMDA-PatA is most effective against.

Original article

Nature communications doi: 10.1038/s41467-024-51635-9

H. Saito, Y. Handa, M. Chen, T. Schneider-Poetsch, Y. Shichino, M. Takahashi, D. Romo, M. Yoshida, A. Fürstner, T. Ito, K. Fukuzawa, S. Iwasaki,

"DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs".

Contact

Minoru Yoshida; Group Director
Tilman Schneider-Poetsch; Senior Research Scientist
Chemical Genomics Research Group