Stress given by abnormal proteins derived from introns

September 14, 2021

Anticancer mechanisms by splicing regulatory compounds elucidated

RIKEN Cluster for Pioneering Research and RIKEN CSRS have identified a series of mechanisms where splicing modulator spliceostatin A (SSA) induces translation from introns and suppresses the entire synthesis of proteins through the formation of aggregates of abnormal proteins.

Some splicing modulating compounds have a potential to be used as therapeutic agents for cancer. However, the relationship between splicing modulating activities and anticancer activities of splicing modulators has not yet been fully understood.

The research group comprehensively identified truncated abnormal proteins derived from intron sequences from cells treated with SSA, a splicing modulator. From the findings, the group found that the truncated proteins intrinsically form condensates and inactivate mTORC1, a complex that governs signaling.

The study identified a part of the anticancer mechanisms of splicing modulators, which should contribute to the development of anticancer drugs.

Original article
Cell Chemical Biology doi:10.1016/j.chembiol.2021.07.015
J. K. Chhipi-Shrestha, T. Schneider-Poetsch, T. Suzuki, M. Mito, K. Khan, N. Dohmae, S. Iwasaki, M. Yoshida,
"Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns".
Minoru Yoshida
Group Director
Chemical Genomics Research Group