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Oct. 19, 2007 Research Highlight Biology

A new way to tackle tumors

Japanese researchers find compound disrupts mRNA quality control

Schematic showing the role of spliceosome subcomplex SF3b Figure 1: The spliceosome subcomplex SF3b plays an active role in splicing mRNA, and in preventing pre-mRNA from leaving the nucleus. It is inhibited by spliceostatin.

Researchers from RIKEN and several other Japanese institutions have unraveled a mechanism of action of a family of powerful anti-tumor drugs, which they have named spliceostatins. These compounds disrupt part of the quality control system by which cells ensure that messenger RNA (mRNA)—the genetic material used to transfer the plans for making proteins from the DNA to where they are built—is not defective.

The work raises the possibility of spliceostatins being used not only as the basis of drugs to fight cancer and as antiviral agents, but also as tools for analyzing the effectiveness of the quality control system itself.

The sequence for a protein printed off the nuclear DNA typically comes in sections separated by intervening segments of nonsense, known as introns. The introns must be chopped out and the remaining sections joined together to form a viable code for transfer to the ribosomes outside the nucleus where proteins are made. This splicing action is performed by a multi-component complex known as the spliceosome.

The spliceosome has to work efficiently and accurately as code containing introns (pre-mRNA) leads to aberrant proteins which can be harmful, even lethal. As a second line of defense to protect the health of the cell, intron-containing genetic material is blocked from going through the membrane which surrounds the nucleus.

In a recent paper in Nature Chemical Biology 1, the researchers from the RIKEN Discovery Research Institute in Wako, several Japanese universities, Astellas Pharma Inc. and the Japanese Science and Technology Corporation detail how they labeled spliceostatin A with biotin and used this combination to determine that spliceostatins bind to proteins of the SF3b subcomplex of the spliceosome.

They found that not only was spliceosome activity inhibited when spliceostatin A was attached to SF3b, but intron-containing genetic material accumulated both inside and outside the nucleus, and that proteins including intron-derived sequences were generated (Fig. 1). So treatment with spliceostatin allows synthesis of potentially harmful proteins. Direct inhibition of the SF3b subcomplex using interference RNA led to the same outcomes.

Interestingly, while spliceostatin treatment appears to be lethal to tumor cells, its effects are milder in other cells. “We would now like to elucidate how the drug exerts its potent anticancer activity,” says project leader, Minoru Yoshida of RIKEN, “and also how its target, SF3b is involved in the security system which prevents leakage of pre-mRNA from the nucleus.”

References

  • 1. Kaida, D., Motoyoshi , H., Tashiro, E., Nojima, T., Hagiwara, M., Ishigami, K., Watanabe, H., Kitahara, T., Yoshida, T., Nakajima, H., Tani, T., Horinouchi, S. & Yoshida, M. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nature Chemical Biology 3, 576–583 (2007). doi: 10.1038/nchembio.2007.18

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