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Review

Pre-mRNA splicing-associated diseases and therapies

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 525-538 | Accepted 18 Jul 2023, Published online: 01 Aug 2023

References

  • Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291(5507):1304–1351. doi: 10.1126/science.1058040
  • Pertea M, Salzberg SL. Between a chicken and a grape: estimating the number of human genes. Genome Biol. 2010;11(5):206. doi: 10.1186/gb-2010-11-5-206
  • Hnilicova J, Stanek D. Where splicing joins chromatin. Nucleus. 2011;2(3):182–188. doi: 10.4161/nucl.2.3.15876
  • Gehring NH, Roignant JY. Anything but ordinary – emerging splicing mechanisms in eukaryotic gene regulation. Trends Genet. 2021;37(4):355–372. doi: 10.1016/j.tig.2020.10.008
  • Matlin AJ, Clark F, Smith CWJ. Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol. 2005;6(5):386–398. doi: 10.1038/nrm1645
  • Wang ET, Sandberg R, Luo S, et al. Alternative isoform regulation in human tissue transcriptomes. Nature. 2008;456(7221):470–476. doi: 10.1038/nature07509
  • Sinitcyn P, Richards AL, Weatheritt RJ, et al. Global detection of human variants and isoforms by deep proteome sequencing. Nat Biotechnol. 2023. doi:10.1038/s41587-023-01714-x.
  • Nilsen TW, Graveley BR. Expansion of the eukaryotic proteome by alternative splicing. Nature. 2010;463(7280):457–463. doi: 10.1038/nature08909
  • Moore MJ, Sharp PA. Evidence for two active sites in the spliceosome provided by stereochemistry of pre-mRNA splicing. Nature. 1993;365(6444):364–368. doi: 10.1038/365364a0
  • Plaschka C, Newman AJ, Nagai K. Structural basis of nuclear pre-mRNA splicing: lessons from yeast. Cold Spring Harb Perspect Biol. 2019;11(5):11. doi: 10.1101/cshperspect.a032391
  • Kastner B, Will CL, Stark H, et al. Structural insights into nuclear pre-mRNA splicing in higher eukaryotes. Cold Spring Harb Perspect Biol. 2019;11(11):11. doi: 10.1101/cshperspect.a032417
  • Carvill GL, Mefford HC. Poison exons in neurodevelopment and disease. Curr Opin Genet Dev. 2020;65:98–102. doi: 10.1016/j.gde.2020.05.030
  • Kurosaki T, Popp MW, Maquat LE. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat Rev Mol Cell Biol. 2019;20(7):406–420. doi: 10.1038/s41580-019-0126-2
  • Turunen JJ, Niemela EH, Verma B, et al. The significant other: splicing by the minor spliceosome. Wiley Interdiscip Rev RNA. 2013;4(1):61–76. doi: 10.1002/wrna.1141
  • Brow DA. Allosteric cascade of spliceosome activation. Ann Rev Genet. 2002;36(1):333–360. doi: 10.1146/annurev.genet.36.043002.091635
  • Hogg R, McGrail JC, O'Keefe RT. The function of the NineTeen Complex (NTC) in regulating spliceosome conformations and fidelity during pre-mRNA splicing. Biochem Soc Trans. 2010;38(4):1110–1115. doi: 10.1042/BST0381110
  • Staley JP, Guthrie C. Mechanical devices of the spliceosome: motors, clocks, springs, and things. Cell. 1998;92(3):315–326. doi: 10.1016/S0092-8674(00)80925-3
  • De Bortoli F, Espinosa S, Zhao R. DEAH-Box RNA helicases in pre-mRNA splicing. Trends Biochem Sci. 2021;46(3):225–238. doi: 10.1016/j.tibs.2020.10.006
  • Wahl MC, Will CL, Luhrmann R. The spliceosome: design principles of a dynamic RNP machine. Cell. 2009;136(4):701–718. doi: 10.1016/j.cell.2009.02.009
  • Hoskins AA, Friedman LJ, Gallagher SS, et al. Ordered and dynamic assembly of single spliceosomes. Science. 2011;331(6022):1289–1295. doi: 10.1126/science.1198830
  • Hoskins AA, Rodgers ML, Friedman LJ, et al. Single molecule analysis reveals reversible and irreversible steps during spliceosome activation. Elife. 2016;5: doi: 10.7554/eLife.14166
  • Fu X, Kaur H, Rodgers ML, et al. Identification of transient intermediates during spliceosome activation by single molecule fluorescence microscopy. Proc Natl Acad Sci U S A. 2022;119(48):e2206815119. doi: 10.1073/pnas.2206815119
  • Braun JE, Friedman LJ, Gelles J, et al. Synergistic assembly of human pre-spliceosomes across introns and exons. Elife. 2018;7: doi: 10.7554/eLife.37751
  • Abelson J, Blanco M, Ditzler MA, et al. Conformational dynamics of single pre-mRNA molecules during in vitro splicing. Nat Struct Mol Biol. 2010;17(4):504–512. doi: 10.1038/nsmb.1767
  • Tseng CK, Cheng SC. Both catalytic steps of nuclear pre-mRNA splicing are reversible. Science. 2008;320(5884):1782–1784. doi: 10.1126/science.1158993
  • Sales-Lee J, Perry DS, Bowser BA, et al. Coupling of spliceosome complexity to intron diversity. Curr Biol. 2021;31(22):4898–4910.e4. doi: 10.1016/j.cub.2021.09.004
  • Fabrizio P, Dannenberg J, Dube P, et al. The evolutionarily conserved core design of the catalytic activation step of the yeast spliceosome. Mol Cell. 2009;36(4):593–608. doi: 10.1016/j.molcel.2009.09.040
  • Robberson BL, Cote GJ, Berget SM. Exon definition may facilitate splice site selection in RNAs with multiple exons. Mol Cell Biol. 1990;10(1):84–94. doi: 10.1128/MCB.10.1.84
  • Li X, Liu S, Zhang L, et al. A unified mechanism for intron and exon definition and back-splicing. Nature. 2019;573(7774):375–380. doi: 10.1038/s41586-019-1523-6
  • Takeiwa T, Mitobe Y, Ikeda K, et al. Roles of splicing factors in hormone-related cancer progression. Int J Mol Sci. 2020;21(5):21. doi: 10.3390/ijms21051551
  • Soemedi R, Cygan KJ, Rhine CL, et al. Pathogenic variants that alter protein code often disrupt splicing. Nat Genet. 2017;49(6):848–855. doi: 10.1038/ng.3837
  • Cartegni L, Chew SL, Krainer AR. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet. 2002;3(4):285–298. doi: 10.1038/nrg775
  • Srebrow A, Kornblihtt AR. The connection between splicing and cancer. J Cell Sci. 2006;119(13):2635–2641. doi: 10.1242/jcs.03053
  • Anna A, Monika G. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet. 2018;59(3):253–268. doi: 10.1007/s13353-018-0444-7
  • Scotti MM, Swanson MS. RNA mis-splicing in disease. Nat Rev Genet. 2016;17(1):19–32. doi: 10.1038/nrg.2015.3
  • Orengo JP, Cooper TA. Alternative splicing in disease. Adv Exp Med Biol. 2007;623:212–223.
  • Singh RK, Cooper TA. Pre-mRNA splicing in disease and therapeutics. Trends Mol Med. 2012;18(8):472–482. doi: 10.1016/j.molmed.2012.06.006
  • Agrawal AA, Yu L, Smith PG, et al. Targeting splicing abnormalities in cancer. Curr Opin Genet Dev. 2018;48:67–74. doi: 10.1016/j.gde.2017.10.010
  • Griffin C, Saint-Jeannet JP. Spliceosomopathies: Diseases and mechanisms. Dev Dyn. 2020;249(9):1038–1046. doi: 10.1002/dvdy.214
  • Mabin JW, Lewis PW, Brow DA, et al. Human spliceosomal snRNA sequence variants generate variant spliceosomes. RNA. 2021;27(10):1186–1203. doi: 10.1261/rna.078768.121
  • Dvinge H, Guenthoer J, Porter PL, et al. RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing. Genome Res. 2019;29(10):1591–1604. doi: 10.1101/gr.246678.118
  • Suzuki H, Kumar SA, Shuai S, et al. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature. 2019;574(7780):707–711. doi: 10.1038/s41586-019-1650-0
  • Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465–472. doi: 10.1007/s00401-011-0922-z
  • Kogerman P, Krause D, Rahnama F, et al. Alternative first exons of PTCH1 are differentially regulated in vivo and may confer different functions to the PTCH1 protein. Oncogene. 2002;21(39):6007–6016. doi: 10.1038/sj.onc.1205865
  • Sasaki H, Nishizaki Y, Hui C, et al. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development. 1999;126(17):3915–3924. doi: 10.1242/dev.126.17.3915
  • Shuai S, Suzuki H, Diaz-Navarro A, et al. The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature. 2019;574(7780):712–716. doi: 10.1038/s41586-019-1651-z
  • Kudinov AE, Karanicolas J, Golemis EA, et al. Musashi RNA-Binding proteins as cancer drivers and novel therapeutic targets. Clin Cancer Res. 2017;23(9):2143–2153. doi: 10.1158/1078-0432.CCR-16-2728
  • van der Feltz C, Hoskins AA. Structural and functional modularity of the U2 snRNP in pre-mRNA splicing. Crit Rev Biochem Mol Biol. 2019;54(5):443–465. doi: 10.1080/10409238.2019.1691497
  • Tholen J, Galej WP. Structural studies of the spliceosome: Bridging the gaps. Curr Opin Struct Biol. 2022;77:102461. doi: 10.1016/j.sbi.2022.102461
  • Tholen J, Razew M, Weis F, et al. Structural basis of branch site recognition by the human spliceosome. Science. 2022;375(6576):50–57. doi: 10.1126/science.abm4245
  • Cretu C, Gee P, Liu X, et al. Structural basis of intron selection by U2 snRNP in the presence of covalent inhibitors. Nat Commun. 2021;12(1):4491. doi: 10.1038/s41467-021-24741-1
  • Schmitzova J, Cretu C, Dienemann C, et al. Structural basis of catalytic activation in human splicing. Nature. 2023;617(7962):842–850. doi: 10.1038/s41586-023-06049-w
  • Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478(7367):64–69. doi: 10.1038/nature10496
  • Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet. 2011;44(1):47–52. doi: 10.1038/ng.1032
  • Hahn CN, Scott HS. Spliceosome mutations in hematopoietic malignancies. Nat Genet. 2011;44(1):9–10. doi: 10.1038/ng.1045
  • Dvinge H, Kim E, Abdel-Wahab O, et al. RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer. 2016;16(7):413–430. doi: 10.1038/nrc.2016.51
  • Seiler M, Peng S, Agrawal AA, et al. Somatic mutational landscape of splicing factor genes and their functional consequences across 33 cancer types. Cell Rep. 2018;23(1):282–296.e4. doi: 10.1016/j.celrep.2018.01.088
  • Darman RB, Seiler M, Agrawal AA, et al. Cancer-associated SF3B1 hotspot mutations induce cryptic 3′ splice site selection through use of a different branch point. Cell Rep. 2015;13(5):1033–1045. doi: 10.1016/j.celrep.2015.09.053
  • DeBoever C, Ghia EM, Shepard PJ, et al. Transcriptome sequencing reveals potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers. PLoS Comput Biol. 2015;11(3):e1004105. doi: 10.1371/journal.pcbi.1004105
  • Tang Q, Rodriguez-Santiago S, Wang J, et al. SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing. Genes Dev. 2016;30(24):2710–2723. doi: 10.1101/gad.291872.116
  • Carrocci TJ, Zoerner DM, Paulson JC, et al. Sf3b1 mutations associated with myelodysplastic syndromes alter the fidelity of branchsite selection in yeast. Nucleic Acids Res. 2017;45:4837–4852. doi: 10.1093/nar/gkw1349
  • Zhang Z, Will CL, Bertram K, et al. Molecular architecture of the human 17S U2 snRNP. Nature. 2020;583(7815):310–313. doi: 10.1038/s41586-020-2344-3
  • Zhang J, Ali AM, Lieu YK, et al. Disease-causing mutations in SF3B1 alter splicing by disrupting interaction with SUGP1. Mol Cell. 2019;76(1):82–95.e7. doi: 10.1016/j.molcel.2019.07.017
  • Zhang J, Huang J, Xu K, et al. DHX15 is involved in SUGP1-mediated RNA missplicing by mutant SF3B1 in cancer. Proc Natl Acad Sci U S A. 2022;119(49):e2216712119. doi: 10.1073/pnas.2216712119
  • Beusch I, Rao B, Studer M, et al. Targeted high-throughput mutagenesis of the human spliceosome reveals its in vivo operating principles. Mol Cell. 2023;83(14):2578–2594.e9. Online Ahead of Print. doi: 10.1016/j.molcel.2023.06.003
  • Feng Q, Krick K, Chu J, et al. Splicing quality control mediated by DHX15 and its G-patch activator, SUGP1. bioRxiv 2022:2022.11.14.516533.
  • Pellagatti A, Boultwood J. SF3B1 mutant myelodysplastic syndrome: Recent advances. Adv Biol Regul. 2021;79:100776. doi: 10.1016/j.jbior.2020.100776
  • Lee SC, North K, Kim E, et al. Synthetic lethal and convergent biological effects of cancer-associated spliceosomal gene mutations. Cancer Cell. 2018;34(2):225–241.e8. doi: 10.1016/j.ccell.2018.07.003
  • Inoue D, Chew GL, Liu B, et al. Spliceosomal disruption of the non-canonical BAF complex in cancer. Nature. 2019;574(7778):432–436. doi: 10.1038/s41586-019-1646-9
  • North K, Benbarche S, Liu B, et al. Synthetic introns enable splicing factor mutation-dependent targeting of cancer cells. Nat Biotechnol. 2022;40(7):1103–1113. doi: 10.1038/s41587-022-01224-2
  • Wood KA, Eadsforth MA, Newman WG, et al. The role of the U5 snRNP in genetic disorders and cancer. Front Genet. 2021;12:636620. doi: 10.3389/fgene.2021.636620
  • He H, Liyanarachchi S, Akagi K, et al. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science. 2011;332(6026):238–240. doi: 10.1126/science.1200587
  • Jafarifar F, Dietrich RC, Hiznay JM, et al. Biochemical defects in minor spliceosome function in the developmental disorder MOPD I. RNA. 2014;20(7):1078–1089. doi: 10.1261/rna.045187.114
  • Grainger RJ, Beggs JD. Prp8 protein: at the heart of the spliceosome. RNA. 2005;11(5):533–557. doi: 10.1261/rna.2220705
  • Francis PJ. Genetics of inherited retinal disease. J R Soc Med. 2006;99(4):189–191. doi: 10.1177/014107680609900417
  • McKie AB, McHale JC, Keen TJ, et al. Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13). Hum Mol Genet. 2001;10(15):1555–1562. doi: 10.1093/hmg/10.15.1555
  • Mayerle M, Guthrie C. Prp8 retinitis pigmentosa mutants cause defects in the transition between the catalytic steps of splicing. RNA. 2016;22(5):793–809. doi: 10.1261/rna.055459.115
  • Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013;84(2):132–141. doi: 10.1111/cge.12203
  • Boon KL, Grainger RJ, Ehsani P, et al. Prp8 mutations that cause human retinitis pigmentosa lead to a U5 snRNP maturation defect in yeast. Nat Struct Mol Biol. 2007;14(11):1077–1083. doi: 10.1038/nsmb1303
  • Maeder C, Kutach AK, Guthrie C. ATP-dependent unwinding of U4/U6 snRnas by the Brr2 helicase requires the C terminus of Prp8. Nat Struct Mol Biol. 2009;16(1):42–48. doi: 10.1038/nsmb.1535
  • Mozaffari-Jovin S, Wandersleben T, Santos KF, et al. Inhibition of RNA helicase Brr2 by the C-terminal tail of the spliceosomal protein Prp8. Science. 2013;341(6141):80–84. doi: 10.1126/science.1237515
  • Korir PK, Roberts L, Ramesar R, et al. A mutation in a splicing factor that causes retinitis pigmentosa has a transcriptome-wide effect on mRNA splicing. BMC Res Notes. 2014;7(1):401. doi: 10.1186/1756-0500-7-401
  • Krausova M, Kreplova M, Banik P, et al. Retinitis pigmentosa–associated mutations in mouse Prpf8 cause misexpression of circRnas and degeneration of cerebellar granule cells. Life Sci Alliance. 2023;6(6):6. doi: 10.26508/lsa.202201855
  • Vithana EN, Abu-Safieh L, Allen MJ, et al. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol Cell. 2001;8(2):375–381. doi: 10.1016/S1097-2765(01)00305-7
  • Yang C, Georgiou M, Atkinson R, et al. Pre-mRNA processing factors and retinitis pigmentosa: RNA splicing and beyond. Front Cell Dev Biol. 2021;9:700276. doi: 10.3389/fcell.2021.700276
  • Maxwell DW, O'Keefe RT, Roy S, et al. The role of splicing factors in retinitis pigmentosa: links to cilia. Biochem Soc Trans. 2021;49(3):1221–1231. doi: 10.1042/BST20200798
  • Shchepachev V, Azzalin CM. The Mpn1 RNA exonuclease: cellular functions and implication in disease. FEBS Lett. 2013;587(13):1858–1862. doi: 10.1016/j.febslet.2013.05.005
  • Volpi L, Roversi G, Colombo EA, et al. Targeted next-generation sequencing appoints c16orf57 as clericuzio-type poikiloderma with neutropenia gene. Am J Hum Genet. 2010;86(1):72–76. doi: 10.1016/j.ajhg.2009.11.014
  • Shchepachev V, Wischnewski H, Missiaglia E, et al. Mpn1, mutated in poikiloderma with neutropenia protein 1, is a conserved 3′-to-5′ RNA exonuclease processing u6 small nuclear RNA. Cell Rep. 2012;2(4):855–865. doi: 10.1016/j.celrep.2012.08.031
  • Didychuk AL, Butcher SE, Brow DA. The life of U6 small nuclear RNA, from cradle to grave. RNA. 2018;24(4):437–460. doi: 10.1261/rna.065136.117
  • Shchepachev V, Wischnewski H, Soneson C, et al. Human Mpn1 promotes post-transcriptional processing and stability of U6atac. FEBS Lett. 2015;589(18):2417–2423. doi: 10.1016/j.febslet.2015.06.046
  • Mroczek S, Krwawicz J, Kutner J, et al. C16orf57 , a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3′ end modification. Genes Dev. 2012;26(17):1911–1925. doi: 10.1101/gad.193169.112
  • Hilcenko C, Simpson PJ, Finch AJ, et al. Aberrant 3′ oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia. Blood. 2013;121(6):1028–1038. doi: 10.1182/blood-2012-10-461491
  • Patil P, Uechi T, Kenmochi N. Incomplete splicing of neutrophil-specific genes affects neutrophil development in a zebrafish model of poikiloderma with neutropenia. RNA Biol. 2015;12(4):426–434. doi: 10.1080/15476286.2015.1017240
  • Childs-Disney JL, Yang X, Gibaut QMR, et al. Targeting RNA structures with small molecules. Nat Rev Drug Discov. 2022;21(10):736–762. doi: 10.1038/s41573-022-00521-4
  • Desterro J, Bak-Gordon P, Carmo-Fonseca M. Targeting mRNA processing as an anticancer strategy. Nat Rev Drug Discov. 2020;19(2):112–129. doi: 10.1038/s41573-019-0042-3
  • Bhat B, Karve S, Anderson DG. mRNA therapeutics: beyond vaccine applications. Trends Mol Med. 2021;27(9):923–924. doi: 10.1016/j.molmed.2021.05.004
  • Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203–222. doi: 10.1038/nrd.2016.246
  • Bennett CF, Krainer AR, Cleveland DW. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu Rev Neurosci. 2019;42(1):385–406. doi: 10.1146/annurev-neuro-070918-050501
  • Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723–1732. doi: 10.1056/NEJMoa1702752
  • Hastings ML, Berniac J, Liu YH, et al. Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. Sci Transl Med. 2009;1(5):5ra12. doi: 10.1126/scitranslmed.3000208
  • Palacino J, Swalley SE, Song C, et al. SMN2 splice modulators enhance U1–pre-pre-mRNA association and rescue SMA mice. Nat Chem Biol. 2015;11(7):511–517. doi: 10.1038/nchembio.1837
  • Naryshkin NA, Weetall M, Dakka A, et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science. 2014;345(6197):688–693. doi: 10.1126/science.1250127
  • Krach F, Stemick J, Boerstler T, et al. An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington's disease patient neurons. Nat Commun. 2022;13(1):6797. doi: 10.1038/s41467-022-34419-x
  • https://classic.clinicaltrials.gov/ct2/show/NCT05358717
  • Ratni H, Ebeling M, Baird J, et al. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) gene splicing modifier for the treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018;61(15):6501–6517. doi: 10.1021/acs.jmedchem.8b00741
  • Ratni H, Scalco RS, Stephan AH. Risdiplam, the first approved small molecule splicing modifier drug as a blueprint for future transformative medicines. ACS Med Chem Lett. 2021;12(6):874–877. doi: 10.1021/acsmedchemlett.0c00659
  • Sivaramakrishnan M, McCarthy KD, Campagne S, et al. Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Nat Commun. 2017;8(1):1476. doi: 10.1038/s41467-017-01559-4
  • Campagne S, Boigner S, Rudisser S, et al. Structural basis of a small molecule targeting RNA for a specific splicing correction. Nat Chem Biol. 2019;15(12):1191–1198. doi: 10.1038/s41589-019-0384-5
  • Bhattacharyya A, Trotta CR, Narasimhan J, et al. Small molecule splicing modifiers with systemic HTT-lowering activity. Nat Commun. 2021;12(1):7299. doi: 10.1038/s41467-021-27157-z
  • Ishigami Y, Wong MS, Martí-Gómez C, et al. Specificity, synergy, and mechanisms of splice-modifying drugs. 2023. bioRxiv 2022:2022.12.30.522303.
  • Roca X, Akerman M, Gaus H, et al. Widespread recognition of 5′ splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides. Genes Dev. 2012;26(10):1098–1109. doi: 10.1101/gad.190173.112
  • Monteys AM, Hundley AA, Ranum PT, et al. Regulated control of gene therapies by drug-induced splicing. Nature. 2021;596(7871):291–295. doi: 10.1038/s41586-021-03770-2
  • Zhang L, Xie X, Djokovic N, et al. Reversible control of RNA splicing by photoswitchable small molecules. J Am Chem Soc. 2023;145(23):12783–12792. doi: 10.1021/jacs.3c03275
  • Effenberger KA, Urabe VK, Jurica MS. Modulating splicing with small molecular inhibitors of the spliceosome. Wiley Interdiscip Rev RNA. 2017;8(2):e1381. doi: 10.1002/wrna.1381
  • Nakajima H, Hori Y, Terano H, et al. New antitumor substances, FR901463, FR901464 and FR901465. II. Activities against experimental tumors in mice and mechanism of action. J Antibiot (Tokyo). 1996;49(12):1204–1211. doi: 10.7164/antibiotics.49.1204
  • Mizui Y, Sakai T, Iwata M, et al. Pladienolides, new substances from culture of Streptomyces platensis Mer-11107 III. In vitro and in vivo antitumor activities. J Antibiot. 2004;57(3):188–196. doi: 10.7164/antibiotics.57.188
  • Sakai Y, Tsujita T, Akiyama T, et al. GEX1 compounds, novel antitumor antibiotics related to herboxidiene, produced by Streptomyces sp. II. The effects on cell cycle progression and gene expression. J Antibiot (Tokyo). 2002;55(10):863–872. doi: 10.7164/antibiotics.55.863
  • Eustaquio AS, Janso JE, Ratnayake AS, et al. Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase. Proc Natl Acad Sci U S A. 2014;111(33):E3376–85. doi: 10.1073/pnas.1408300111
  • Masato H, Hajime M, Hidenori W, et al. A synthesis of FR901464. Tetrahedron Lett. 2001;42(46):8207–8210. doi: 10.1016/S0040-4039(01)01763-4
  • Kotake Y, Sagane K, Owa T, et al. Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat Chem Biol. 2007;3(9):570–575. doi: 10.1038/nchembio.2007.16
  • Hasegawa M, Miura T, Kuzuya K, et al. Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product. ACS Chem Biol. 2011;6(3):229–233. doi: 10.1021/cb100248e
  • Kaida D, Motoyoshi H, Tashiro E, et al. Spliceostatin a targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat Chem Biol. 2007;3(9):576–583. doi: 10.1038/nchembio.2007.18
  • Teng T, Tsai JH, Puyang X, et al. Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A–SF3b complex. Nat Commun. 2017;8(1):15522. doi: 10.1038/ncomms15522
  • Effenberger KA, Urabe VK, Prichard BE, et al. Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages. RNA. 2016;22(3):350–359. doi: 10.1261/rna.053108.115
  • Osman S, Albert BJ, Wang Y, et al. Structural requirements for the antiproliferative activity of pre-mRNA splicing inhibitor FR901464. Chemistry. 2011;17(3):895–904. doi: 10.1002/chem.201002402
  • Vigevani L, Gohr A, Webb T, et al. Molecular basis of differential 3′ splice site sensitivity to anti-tumor drugs targeting U2 snRNP. Nat Commun. 2017;8(1):2100. doi: 10.1038/s41467-017-02007-z
  • Finci LI, Zhang X, Huang X, et al. The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action. Genes Dev. 2018;32(3–4):309–320. doi: 10.1101/gad.311043.117
  • Cretu C, Agrawal AA, Cook A, et al. Structural basis of splicing modulation by antitumor macrolide compounds. Mol Cell. 2018;70(2):265–273.e8. doi: 10.1016/j.molcel.2018.03.011
  • Carrocci TJ, Paulson JC, Hoskins AA. Functional analysis of Hsh155/SF3b1 interactions with the U2 snRNA/branch site duplex. RNA. 2018;24(8):1028–1040. doi: 10.1261/rna.065664.118
  • Hansen SR, Nikolai BJ, Spreacker PJ, et al. Chemical inhibition of pre-mRNA splicing in living saccharomyces cerevisiae. Cell Chem Biol. 2019;26(3):443–8 e3. doi: 10.1016/j.chembiol.2018.11.008
  • Seiler M, Yoshimi A, Darman R, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24(4):497–504. doi: 10.1038/nm.4493
  • Bowling EA, Wang JH, Gong F, et al. Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer. Cell. 2021;184(2):384–403.e21. doi: 10.1016/j.cell.2020.12.031
  • Steensma DP, Wermke M, Klimek VM, et al. Phase I first-in-human dose escalation study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia. 2021;35(12):3542–3550. doi: 10.1038/s41375-021-01328-9
  • Ten Hacken E, Valentin R, Regis FFD, et al. Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies. JCI Insight. 2018;3(19):3. doi: 10.1172/jci.insight.121438
  • Wheeler EC, Martin BJE, Doyle WC, et al. Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS/AML. Blood. 2022;140(Supplement 1):6888–6889. bioRxiv 2022:2022.09.26.509430. doi: 10.1182/blood-2022-170996
  • Gao Y, Koide K. Chemical perturbation of Mcl-1 pre-mRNA splicing to induce apoptosis in cancer cells. ACS Chem Biol. 2013;8(5):895–900. doi: 10.1021/cb300602j
  • Salton M, Kasprzak WK, Voss T, et al. Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing. Nat Commun. 2015;6(1):7103. doi: 10.1038/ncomms8103
  • Gao Y, Trivedi S, Ferris RL, et al. Regulation of HPV16 E6 and MCL1 by SF3B1 inhibitor in head and neck cancer cells. Sci Rep. 2014;4(1):6098. doi: 10.1038/srep06098
  • Sakamoto KM, Kim KB, Kumagai A, et al. Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A. 2001;98(15):8554–8559. doi: 10.1073/pnas.141230798
  • Calderon-Villalobos LI, Tan X, Zheng N, et al. Auxin perception–structural insights. Cold Spring Harb Perspect Biol. 2010;2(7):a005546. doi: 10.1101/cshperspect.a005546
  • Liu Z, Hu M, Yang Y, et al. An overview of PROTACs: a promising drug discovery paradigm. Mol Biomed. 2022;3(1):46. doi: 10.1186/s43556-022-00112-0
  • Dowhan DH, Hong EP, Auboeuf D, et al. Steroid hormone receptor coactivation and alternative RNA Splicing by U2AF65-related proteins CAPERα and CAPERβ. Mol Cell. 2005;17(3):429–439. doi: 10.1016/j.molcel.2004.12.025
  • Stepanyuk GA, Serrano P, Peralta E, et al. UHM–ULM interactions in the RBM39–U2AF65 splicing-factor complex. Acta Crystallogr D Struct Biol. 2016;72(4):497–511. doi: 10.1107/S2059798316001248
  • Loerch S, Maucuer A, Manceau V, et al. Cancer-relevant Splicing Factor CAPERα Engages the essential splicing factor SF3b155 in a specific ternary complex. J Biol Chem. 2014;289(25):17325–17337. doi: 10.1074/jbc.M114.558825
  • Owa T, Yoshino H, Okauchi T, et al. Discovery of novel antitumor sulfonamides targeting G1 phase of the cell cycle. J Med Chem. 1999;42(19):3789–3799. doi: 10.1021/jm9902638
  • Han T, Goralski M, Gaskill N, et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science. 2017;356(6336). doi: 10.1126/science.aal3755
  • Uehara T, Minoshima Y, Sagane K, et al. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat Chem Biol. 2017;13(6):675–680. doi: 10.1038/nchembio.2363
  • Faust TB, Yoon H, Nowak RP, et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat Chem Biol. 2020;16(1):7–14. doi: 10.1038/s41589-019-0378-3
  • Du X, Volkov OA, Czerwinski RM, et al. Structural basis and kinetic pathway of RBM39 Recruitment to DCAF15 by a sulfonamide molecular glue E7820. Structure. 2019;27(11):1625–1633.e3. doi: 10.1016/j.str.2019.10.005
  • Bussiere DE, Xie L, Srinivas H, et al. Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat Chem Biol. 2020;16(1):15–23. doi: 10.1038/s41589-019-0411-6
  • Xu C, Chen X, Zhang X, et al. RNA-binding protein 39: a promising therapeutic target for cancer. Cell Death Discov. 2021;7(1):214. doi: 10.1038/s41420-021-00598-7
  • Wang E, Lu SX, Pastore A, et al. Targeting an RNA-Binding protein network in acute myeloid leukemia. Cancer Cell. 2019;35(3):369–384.e7. doi: 10.1016/j.ccell.2019.01.010
  • Singh S, Quarni W, Goralski M, et al. Targeting the spliceosome through RBM39 degradation results in exceptional responses in high-risk neuroblastoma models. Sci Adv. 2021;7(47):eabj5405. doi: 10.1126/sciadv.abj5405
  • Lu SX, De Neef E, Thomas JD, et al. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. Cell. 2021;184(15):4032–4047.e31. doi: 10.1016/j.cell.2021.05.038
  • Dahui Q. Next-generation sequencing and its clinical application. Cancer Biol Med. 2019;16(1):4–10. doi: 10.20892/j.issn.2095-3941.2018.0055
  • Anczukow O, Krainer AR. The spliceosome, a potential Achilles heel of MYC-driven tumors. Genome Med. 2015;7(1):107. doi: 10.1186/s13073-015-0234-3
  • Maji D, Grossfield A, Kielkopf CL. Structures of SF3b1 reveal a dynamic Achilles heel of spliceosome assembly: Implications for cancer-associated abnormalities and drug discovery. Biochim Biophys Acta, Gene Regul Mech. 2019;1862(11–12):194440. doi: 10.1016/j.bbagrm.2019.194440
  • Arbab M, Matuszek Z, Kray KM, et al. Base editing rescue of spinal muscular atrophy in cells and in mice. Science. 2023;380(6642):eadg6518. doi: 10.1126/science.adg6518