Inhibition of SF3B1 by molecules targeting the spliceosome results in massive aberrant exon skipping

RNA
Gang WuPhilip M Potter

Abstract

The recent identification of compounds that interact with the spliceosome (sudemycins, spliceostatin A, and meayamycin) indicates that these molecules modulate aberrant splicing via SF3B1 inhibition. Through whole transcriptome sequencing, we have demonstrated that treatment of Rh18 cells with sudemycin leads to exon skipping as the predominant aberrant splicing event. This was also observed following reanalysis of published RNA-seq data sets derived from HeLa cells after spliceostatin A exposure. These results are in contrast to previous reports that indicate that intron retention was the major consequence of SF3B1 inhibition. Analysis of the exon junctions up-regulated by these small molecules indicated that these sequences were absent in annotated human genes, suggesting that aberrant splicing events yielded novel RNA transcripts. Interestingly, the length of preferred downstream exons was significantly longer than the skipped exons, although there was no difference between the lengths of introns flanking skipped exons. The reading frame of the aberrantly skipped exons maintained a ratio of 2:1:1, close to that of the cassette exons (3:1:1) present in naturally occurring isoforms, suggesting negative selection by the nonsens...Continue Reading

References

Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Jul 24, 2007·Nature Chemical Biology·Daisuke KaidaMinoru Yoshida
Mar 20, 2009·Genome Biology·Martin AkermanYael Mandel-Gutfreund
Nov 18, 2009·The Journal of Pathology·Amanda J Ward, Thomas A Cooper
Mar 4, 2010·Genome Biology·Mark D Robinson, Alicia Oshlack
Jun 10, 2010·Nucleic Acids Research·Gabriel A Roybal, Melissa S Jurica
Aug 24, 2010·Cancer Science·Ryohei FurumaiMinoru Yoshida
Dec 9, 2010·ACS Chemical Biology·Makoto HasegawaTamio Mizukami
Feb 25, 2011·ACS Chemical Biology·Liying FanPhilip M Potter
Jul 14, 2011·Genome Research·Timothy Sterne-WeilerJeremy R Sanford
Sep 6, 2011·Nature Structural & Molecular Biology·Sandra Bento MartinsMaria Carmo-Fonseca
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Jul 13, 2013·Nature·Debashish RayTimothy R Hughes
Aug 29, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ferry A L M EskensJosep Tabernero
Dec 12, 2013·Journal of Medicinal Chemistry·Chandraiah LagisettiThomas R Webb
Jan 25, 2014·Genome Biology·Timothy Sterne-Weiler, Jeremy R Sanford
Mar 14, 2014·Nucleic Acids Research·Paolo ConvertiniStefan Stamm
Sep 28, 2014·Bioinformatics·Simon AndersWolfgang Huber
Dec 7, 2014·Proceedings of the National Academy of Sciences of the United States of America·Shihao ShenYi Xing
Jan 7, 2015·Genome Research·Tim R MercerJohn S Mattick
Jan 22, 2015·Nucleic Acids Research·Matthew E RitchieGordon K Smyth
Mar 15, 2015·PLoS Computational Biology·Christopher DeBoeverKelly A Frazer
Dec 3, 2015·Cell Reports·Chi-Kang TsengPeter Baumann

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Citations

Jul 16, 2019·Human Molecular Genetics·Katherine A WoodRaymond T O'Keefe
Jan 11, 2020·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Ling ZhangJing Liu
Apr 10, 2019·Artificial Cells, Nanomedicine, and Biotechnology·Qianjing ZhangHong Zhang
Oct 16, 2020·Nature Communications·Samuel W BradyJinghui Zhang
Dec 23, 2020·International Journal of Molecular Sciences·Karen S Kim GuisbertEric Guisbert
Aug 5, 2021·The Journal of Antibiotics·Tilman Schneider-PoetschMinoru Yoshida
Jan 22, 2022·Science Advances·Cuijuan HanPanagiotis Ntziachristos

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