New research from the lab of Robin Reed, HMS professor of cell biology, sheds light on cellular gene-processing machinery known as the spliceosome and its role in cancer, and advances a promising front in the search for new cancer drugs.
In 2007, researchers reported that the anticancer drug, E7107 (E7) targeted a component of the spliceosome, a dynamic complex of proteins and RNA in a cell’s nucleus that splices pre-messenger RNA (pre-mRNA), the transcribed form of DNA. How E7 induced anticancer activity when bound to the component, SF3b, remained unclear. In a study published in the March 1 issue of Genes & Development.
Reed and her research team, Eric Folco and Kaitlyn Coil, reported that E7 binds SF3b and impairs spliceosomes. The findings not only implicate spliceosomes in cancer and other human diseases, but also suggest that using drugs such as E7 to selectively modulate spliceosome activity in cancer cells may have therapeutic potential.
In most human genes, intervening sequences called introns interrupt functional exons. During the extensive cut-and-paste process of RNA splicing, introns are clipped and exons are stitched together by a gigantic spliceosome containing several RNA molecules and more than 100 proteins to produce mRNA for gene expression. The SF3b factor tightly anchors the pre-mRNA to spliceosomes.
Reed showed that E7 hampers splicing by loosening the critical RNA–RNA association between a “branch point sequence” in the pre-mRNA and a U2 snRNA in the SF3b/U2-snRNP complex. Reed and team assert that SF3b remodels U2 snRNP to facilitate these RNA–RNA interactions, and that E7 inhibits remodeling.
As reported in a companion paper by Juan Valcárcel at Centre de Regulació Genòmica in Spain, another anticancer drug called spliceostatin A also impairs splicing. Reed’s and Valcárcel’s studies raise intriguing questions—including why E7 targets tumor cells when splicing occurs in both normal and tumor cells. High-resolution structures of SF3b bound to E7 may provide answers and aid in the design of second-generation anticancer drugs.
For more information, students may contact Robin Reed, HMS professor of cell biology, at rreed@hms.harvard.edu.
