title: Sudemycin E influences alternative splicing and changes chromatin modifications.
abstract: Sudemycin E is an analog of the pre-messenger RNA splicing modulator FR901464 and its derivative spliceostatin A. Sudemycin E causes the death of cancer cells through an unknown mechanism. We found that similar to spliceostatin A, sudemycin E binds to the U2 small nuclear ribonucleoprotein (snRNP) component SF3B1. Native chromatin immunoprecipitations showed that U2 snRNPs physically interact with nucleosomes. Sudemycin E induces a dissociation of the U2 snRNPs and decreases their interaction with nucleosomes. To determine the effect on gene expression, we performed genome-wide array analysis. Sudemycin E first causes a rapid change in alternative pre-messenger RNA splicing, which is later followed by changes in overall gene expression and arrest in the G2 phase of the cell cycle. The changes in alternative exon usage correlate with a loss of the H3K36me3 modification in chromatin encoding these exons. We propose that sudemycin E interferes with the ability of U2 snRNP to maintain an H3K36me3 modification in actively transcribed genes. Thus, in addition to the reversible changes in alternative splicing, sudemycin E causes changes in chromatin modifications that result in chromatin condensation, which is a likely contributing factor to cancer cell death.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone, Lexington, KY 40536, USA, Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA and GenoSplice Technology, Hôpital Saint-Louis, Av Claude Vellefaux, 75010 Paris, France.
authors.forename: Paolo
authors.initials: P
authors.lastname: Convertini
authors.forename: Manli
authors.initials: M
authors.lastname: Shen
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
authors.forename: Gustavo
authors.initials: G
authors.lastname: Palacios
authors.forename: Chandraiah
authors.initials: C
authors.lastname: Lagisetti
authors.forename: Pierre
authors.initials: P
authors.lastname: de la Grange
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.forename: Yvonne N
authors.initials: YN
authors.lastname: Fondufe-Mittendorf
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
authors.forename: Stefan
authors.initials: S
authors.lastname: Stamm
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects*; D003603:Cytotoxins / Q000633:toxicity; D004852:Epoxy Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000187:drug effects / Q000378:metabolism; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D003603:Cytotoxins; D004852:Epoxy Compounds; D006657:Histones; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D013141:Spiro Compounds; C000589736:sudemycin E