title: The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region.
abstract: Duplex formation between the branch point-binding region (BBR) of U2 snRNA and the branch point sequence (BPS) in the intron is essential for splicing. Both the BBR and BPS interact with the U2 small nuclear ribonucleoprotein (snRNP)-associated SF3b complex, which is the target of the anti-tumor drug E7107. We show that E7107 blocks spliceosome assembly by preventing tight binding of U2 snRNP to pre-mRNA. E7107 has no apparent effect on U2 snRNP integrity. Instead, E7107 abolishes an ATP-dependent conformational change in U2 snRNP that exposes the BBR. We conclude that SF3b is required for this remodeling, which exposes the BBR for tight U2 snRNP binding to pre-mRNA.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Folco
authors.forename: Kaitlyn E
authors.initials: KE
authors.lastname: Coil
authors.forename: Robin
authors.initials: R
authors.lastname: Reed
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D004852:Epoxy Compounds / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012322:RNA Precursors / Q000378:metabolism; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000378:metabolism*; D017381:Spliceosomes / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; C557411:E 7107; D004852:Epoxy Compounds; D018942:Macrolides; D010750:Phosphoproteins; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human