Jump to content

Poison exon

Add links
From Wikipedia, the free encyclopedia
Certain transcripts contain poison exons that can be incorporated via alternative splicing. Skipping of the poison exon leads to a productive transcript that is translated to protein. Incorporation of the poison exon introduces a premature termination codon into the transcript that leads to degradation of the transcript via nonsense-mediated decay. (PDB: 2N3L)

Poison exons (PEs); also called premature termination codon (PTC) exons or nonsense-mediated decay (NMD) exons] are a class of cassette exons that contain PTCs. Inclusion of a PE in a transcript targets the transcript for degradation via NMD. PEs are generally highly conserved elements of the genome and are thought to have important regulatory roles in biology.[1][2] Targeting PE inclusion or exclusion in certain transcripts is being evaluated as a therapeutic strategy.

Discovery

[edit]

In 2002, a model termed regulated unproductive splicing and translation (RUST) was proposed based on the finding that many (~one-third) alternatively spliced transcripts contain PEs. In this model, coupling alternative splicing to NMD (AS-NMD) is thought to tune transcript levels to regulate protein expression.[3] Alternative splicing may also lead to NMD via other pathways besides PE inclusion, e.g., intron retention.[4][5]

PEs were initially characterized in RNA-binding proteins from the SR protein family.[1][2] Genes for other RNA-binding proteins (RBPs) such as those for heterogenous nuclear ribonucleoprotein (hnRNP) also contain PEs.[2] Numerous chromatin regulators also contain PEs, though these are less conserved than PEs within RBPs such as the SR proteins.[6] Multiple spliceosomal components contain PEs.[7]

PE-containing transcripts generally represent a minority of the overall transcript population, in part due to their active degradation via NMD, though this relative abundance can be elevated upon inhibition of NMD or certain biological states.[2][8][9][10][11] Certain PE-containing transcripts are resistant to NMD and may be translated into truncated proteins.[12]

Regulation

[edit]

Cis-regulatory elements neighboring PEs have been found to affect PE inclusion.[13]

Many proteins whose corresponding genes contain PEs autoregulate PE inclusion in their respective transcripts and thereby control their own levels via a feedback loop.[12][14][15][16][17][18][19] Cross-regulation of PE inclusion has also been observed.[20][21][22]

Differential splicing of PEs is implicated in biological processes such as differentiation,[23][24] neurodevelopment,[25] dispersal of nuclear speckles during hypoxia,[26] tumorigenesis,[24][27] organism growth,[15] and T cell expansion.[28]

Protein kinases that regulate phosphorylation of splicing factors can affect splicing processes, thus kinase inhibitors may affect inclusion of PEs. For example, CMGC kinase inhibitors and CDK9 inhibitors have been found to induce PE inclusion in RBM39.[29]

Small molecules that modulate chromatin accessibility can affect PE inclusion.[30]

Mutations in splicing factors can lead to inclusion of PEs in certain transcripts.[31]

PE inclusion can be regulated by external variables such as temperature and electrical activity. For example, PE inclusion in RBM3 transcript is lowered during hypothermia. This is mediated by temperature-dependent binding of the splicing factor HNRNPH1 to the RBM3 transcript.[9] The neuronal RBPs NOVA1/2 are translocated from the nucleus to the cytoplasm during pilocarpine-induced seizure in mice, and it was found that NOVA1/2 regulates the expression of cryptic PEs.[32] The glycosyltransferase O-GlcNAc transferase is responsible for installing the O-GlcNAc post-translational modification and contains a PE.[33] It has been frequently observed that pharmacological or genetic perturbations that elevate cellular O-GlcNAc levels increase PE inclusion in the OGT transcript.[34]

Disease

[edit]

Proper regulation of PE inclusion and exclusion is important for health. Genetic mutations can affect inclusion of PEs and cause disease. For example, loss of CCAR1 leads to PE inclusion in the FANCA transcript, resulting in a Fanconi anemia phenotype.[35]

Dysregulation of components of the splicing machinery can also cause dysregulation of PE inclusion. Mutations in the splicing factor SF3B1 have been found to promote PE inclusion in BRD9, reducing BRD9 mRNA and protein levels and leading to melanomagenesis.[36] Mutations in U2AF1 promote PE inclusion in EIF4A2, leading to impaired global mRNA translation and acute myeloid leukemia (AML) chemoresistance through the integrated stress response pathway.[37] The splicing factor SRSF6 contains a PE whose skipping is connected to T cell acute lymphoblastic leukemia (T-ALL),[38] and PE inclusion in SRSF10 is linked to acute lymphoblastic leukemia (ALL).[39]

Intronic mutations can lead to PE inclusion, such as in the case of SCN1A, where mutations within intron 20 promote inclusion of the nearby PE 20N, leading to Dravet syndrome-like phenotypes in mouse models.[40][41] An intronic mutation in FLNA has been found to impair binding of the splicing regulator PTBP1, leading to inclusion of a poison exon in FLNA transcripts that causes a brain-specific malformation.[25]

Differential inclusion of PEs in various splicing factor and hnRNP genes has been reported in type 1 diabetes.[42] SRSF2 mutations have been found to promote PE inclusion in the epigenetic regulator EZH2, resulting in impaired hematopoietic differentiation.[43]

Clinical relevance

[edit]

Diagnostics

[edit]

With the advent of next-generation sequencing technologies,[44] diagnostic genetic testing has emerged as a powerful tool to diagnose afflictions associated with specific genetic variants. Many diagnostic genetic testing efforts have focused on exome sequencing.[45] PE annotations may improve the diagnostic yield of these tests for certain diseases. For example, variants that affect PE inclusion in sodium channel genes (SCN1A, SCN2A, and SCN8A) have been found to be associated with epilepsies, and analogous variants in SNRPB have been found to be associated with cerebrocostomandibular syndrome.[46][47]

Therapeutic discovery

[edit]

As PE inclusion results in transcript degradation, targeted PE inclusion or exclusion is being evaluated as a therapeutic strategy.[48] This strategy may prove especially applicable towards targets whose gene products are not easily ligandable such as "undruggable" proteins. Targeting PE inclusion/exlusion has been demonstrated with both small molecules[49][50] and antisense oligonucleotides (ASOs).[24][51] Small molecules may modulate splicing by stabilizing alternative splice sites.[49][52] ASOs may block specific splice sites or target certain cis-regulatory elements to promote splicing at other sites.[53][54] These ASOs may also be referred to as splice-switching oligonucleotides (SSOs).[24][54] ASO walks tiling different ASOs across a gene sequence may be necessary to identify ASOs that have the desired effect on PE inclusion.[51]

Stoke Therapeutics is evaluating a strategy termed Targeted Augmentation of Nuclear Gene Output (TANGO).[51] Targeting exon 20N in SCN1A mRNA with the antisense oligonucleotide zorevunersen (STK-001) blocks inclusion of this PE, leading to elevated levels of the productive SCN1A transcript and the gene product sodium channel protein 1 subunit alpha (NaV1.1). In mouse models of Dravet syndrome, which is driven by mutations in SCN1A,[40][41][55] zorevunersen was able to reduce incidence of electrographic seizures and sudden unexpected death in epilepsy and prolong survival.[56][57] As of October 2024, zorevunersen is being evaluated in phase 2 clinical trials (NCT04740476).[58] Zorevunersen received FDA Breakthrough Therapy Designation in December 2024.[59] Also in December 2024, Stoke Therapeutics disclosed that zorevunersen is generally well tolerated and shows substantial and sustained reductions in convulsive seizure frequency.[60] Stoke Therapeutics expects to launch a phase 3 clinical trial in 2025 evaluating zorevunersen for reduction in seizure frequency as the primary endpoint and cognition and behavioral changes as secondary endpoints.[61]

Stoke Therapeutics is also evaluating the ASO STK-002 for treatment of autosomal dominant optic atrophy (ADOA). STK-002 promotes removal of a PE in the transcript of OPA1, leading to elevated OPA1 protein levels.[62]

Remix Therapeutics developed REM-422, which is an oral small molecule that promotes PE inclusion in the oncogene MYB. REM-422 was discovered through a screening campaign for molecules that promote PE inclusion in MYB. Subsequent in vitro experiments showed that REM-422 selectively facilitates binding of the U1 snRNP complex to oligonucleotides containing the MYB 5' splice site sequence. In various AML cell lines, REM-422 leads to degradation of MYB mRNA and lower MYB protein levels. REM-422 demonstrated antitumor activity in mouse xenograft models of acute myeloid leukemia.[49] As of October 2024, REM-422 is being evaluated in phase 1 clinical trials (NCT06118086, NCT06297941).[63][64] The splicing modulator small molecule risdiplam, originally developed to promote exon 7 inclusion in the SMN2 transcript for treatment of spinal muscular atrophy,[65][66] dose-dependently promotes PE inclusion in the MYB transcript as well.[67]

Rgenta Therapeutics has also developed RGT-61159, an oral small molecule that promotes PE inclusion in MYB, as a potential treatment for adenoid cystic carcinoma (ACC).[68] RGT-61159 is being evaluated in phase 1 clinical trials (NCT06462183).[69]

PTC Therapeutics is evaluating the oral small molecule PTC518 as a treatment for Huntington's disease.[50] PTC518 was well-tolerated and showed dose-dependent decreases in HTT mRNA and HTT protein levels in a phase 1 clinical trial.[70] As of October 2024, PTC518 is being evaluated in phase 2 clinical trials (NCT05358717).[71] In December 2024, Novartis entered a global license and collaboration agreement with PTC Therapeutics for PTC518 with an upfront payment of $1.0 billion and up to $1.9 billion in development, regulatory, and sales milestones.[72]

Therapeutic targeting of poison exon inclusion/exclusion has also been proposed for oncogenic splicing factors,[24][27] BRD9 (for treatment of cancer),[36] SYNGAP1,[73] RBM3 (for treatment of neurodegeneration),[53] and CFTR (for treatment of cystic fibrosis).[74]

References

[edit]
  1. ^ a b Ni, Julie Z.; Grate, Leslie; Donohue, John Paul; Preston, Christine; Nobida, Naomi; O'Brien, Georgeann; Shiue, Lily; Clark, Tyson A.; Blume, John E.; Ares, Manuel (2007-03-15). "Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay". Genes & Development. 21 (6): 708–718. doi:10.1101/gad.1525507. ISSN 0890-9369. PMC 1820944. PMID 17369403.
  2. ^ a b c d Lareau, Liana F.; Inada, Maki; Green, Richard E.; Wengrod, Jordan C.; Brenner, Steven E. (April 2007). "Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements". Nature. 446 (7138): 926–929. Bibcode:2007Natur.446..926L. doi:10.1038/nature05676. ISSN 1476-4687. PMID 17361132.
  3. ^ Lewis, Benjamin P.; Green, Richard E.; Brenner, Steven E. (2003-01-07). "Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans". Proceedings of the National Academy of Sciences. 100 (1): 189–192. Bibcode:2003PNAS..100..189L. doi:10.1073/pnas.0136770100. ISSN 0027-8424. PMC 140922. PMID 12502788.
  4. ^ Wong, Justin J.-L.; Ritchie, William; Ebner, Olivia A.; Selbach, Matthias; Wong, Jason W.H.; Huang, Yizhou; Gao, Dadi; Pinello, Natalia; Gonzalez, Maria; Baidya, Kinsha; Thoeng, Annora; Khoo, Teh-Liane; Bailey, Charles G.; Holst, Jeff; Rasko, John E.J. (August 2013). "Orchestrated Intron Retention Regulates Normal Granulocyte Differentiation". Cell. 154 (3): 583–595. doi:10.1016/j.cell.2013.06.052. PMID 23911323.
  5. ^ Braunschweig, Ulrich; Barbosa-Morais, Nuno L.; Pan, Qun; Nachman, Emil N.; Alipanahi, Babak; Gonatopoulos-Pournatzis, Thomas; Frey, Brendan; Irimia, Manuel; Blencowe, Benjamin J. (November 2014). "Widespread intron retention in mammals functionally tunes transcriptomes". Genome Research. 24 (11): 1774–1786. doi:10.1101/gr.177790.114. PMC 4216919. PMID 25258385.
  6. ^ Yan, Qinghong; Weyn-Vanhentenryck, Sebastien M.; Wu, Jie; Sloan, Steven A.; Zhang, Ye; Chen, Kenian; Wu, Jia Qian; Barres, Ben A.; Zhang, Chaolin (2015-03-03). "Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators". Proceedings of the National Academy of Sciences of the United States of America. 112 (11): 3445–3450. Bibcode:2015PNAS..112.3445Y. doi:10.1073/pnas.1502849112. PMC 4371929. PMID 25737549.
  7. ^ Saltzman, Arneet L.; Kim, Yoon Ki; Pan, Qun; Fagnani, Matthew M.; Maquat, Lynne E.; Blencowe, Benjamin J. (2008-04-28). "Regulation of Multiple Core Spliceosomal Proteins by Alternative Splicing-Coupled Nonsense-Mediated mRNA Decay". Molecular and Cellular Biology. 28 (13): 4320–4330. doi:10.1128/MCB.00361-08. PMC 2447145. PMID 18443041.
  8. ^ Saltzman, Arneet L.; Kim, Yoon Ki; Pan, Qun; Fagnani, Matthew M.; Maquat, Lynne E.; Blencowe, Benjamin J. (2008-04-28). "Regulation of Multiple Core Spliceosomal Proteins by Alternative Splicing-Coupled Nonsense-Mediated mRNA Decay". Molecular and Cellular Biology. 28 (13): 4320–4330. doi:10.1128/MCB.00361-08. PMC 2447145. PMID 18443041.
  9. ^ a b Lin, Julie Qiaojin; Khuperkar, Deepak; Pavlou, Sofia; Makarchuk, Stanislaw; Patikas, Nikolaos; Lee, Flora CY; Zbiegly, Julia M; Kang, Jianning; Field, Sarah F; Bailey, David MD; Freeman, Joshua L; Ule, Jernej; Metzakopian, Emmanouil; Ruepp, Marc-David; Mallucci, Giovanna R (2023-07-17). "HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion". The EMBO Journal. 42 (14): e113168. doi:10.15252/embj.2022113168. ISSN 0261-4189. PMC 10350819. PMID 37248947.
  10. ^ Kalyna, Maria; Simpson, Craig G.; Syed, Naeem H.; Lewandowska, Dominika; Marquez, Yamile; Kusenda, Branislav; Marshall, Jacqueline; Fuller, John; Cardle, Linda; McNicol, Jim; Dinh, Huy Q.; Barta, Andrea; Brown, John W. S. (March 2012). "Alternative splicing and nonsense-mediated decay modulate expression of important regulatory genes in Arabidopsis". Nucleic Acids Research. 40 (6): 2454–2469. doi:10.1093/nar/gkr932. ISSN 1362-4962. PMC 3315328. PMID 22127866.
  11. ^ Carter, Mark S.; Doskow, Jessica; Morris, Phillip; Li, Shulin; Nhim, Ronald P.; Sandstedt, Sara; Wilkinson, Miles F. (December 1995). "A Regulatory Mechanism That Detects Premature Nonsense Codons in T-cell Receptor Transcripts in Vivo Is Reversed by Protein Synthesis Inhibitors in Vitro". Journal of Biological Chemistry. 270 (48): 28995–29003. doi:10.1074/jbc.270.48.28995. PMID 7499432.
  12. ^ a b Königs, Vanessa; Machado, Camila de Oliveira Freitas; Arnold, Benjamin; Blümel, Nicole; Solovyeva, Anfisa; Löbbert, Sinah; Schafranek, Michal; Mozos, Igor Ruiz De Los; Wittig, Ilka; McNicoll, Francois; Schulz, Marcel H.; Müller-McNicoll, Michaela (2020-03-02). "SRSF7 maintains its homeostasis through the expression of Split-ORFs and nuclear body assembly". Nature Structural & Molecular Biology. 27 (3): 260–273. doi:10.1038/s41594-020-0385-9. PMC 7096898. PMID 32123389.
  13. ^ Li, Hao; Ding, Zhan; Fang, Zhuo-Ya; Long, Ni; Ang, Hao-Yang; Zhang, Yu; Fan, Yu-Jie; Xu, Yong-Zhen (2024-06-10). "Conserved intronic secondary structures with concealed branch sites regulate alternative splicing of poison exons". Nucleic Acids Research. 52 (10): 6002–6016. doi:10.1093/nar/gkae185. ISSN 0305-1048. PMC 11162794. PMID 38499485.
  14. ^ Stoilov, P. (2004-01-06). "Human tra2-beta1 autoregulates its protein concentration by influencing alternative splicing of its pre-mRNA". Human Molecular Genetics. 13 (5): 509–524. doi:10.1093/hmg/ddh051. ISSN 1460-2083. PMID 14709600.
  15. ^ a b Belleville, Andrea E.; Thomas, James D.; Tonnies, Jackson; Gabel, Austin M.; Borrero Rossi, Andrea; Singh, Priti; Queitsch, Christine; Bradley, Robert K. (2024-08-16). Copenhaver, Gregory P. (ed.). "An autoregulatory poison exon in Smndc1 is conserved across kingdoms and influences organism growth". PLOS Genetics. 20 (8): e1011363. doi:10.1371/journal.pgen.1011363. ISSN 1553-7404. PMC 11357089. PMID 39150991.
  16. ^ Wollerton, Matthew C; Gooding, Clare; Wagner, Eric J; Garcia-Blanco, Mariano A; Smith, Christopher W.J (January 2004). "Autoregulation of Polypyrimidine Tract Binding Protein by Alternative Splicing Leading to Nonsense-Mediated Decay". Molecular Cell. 13 (1): 91–100. doi:10.1016/S1097-2765(03)00502-1. PMID 14731397.
  17. ^ Rossbach, Oliver; Hung, Lee-Hsueh; Schreiner, Silke; Grishina, Inna; Heiner, Monika; Hui, Jingyi; Bindereif, Albrecht (2009-03-01). "Auto- and Cross-Regulation of the hnRNP L Proteins by Alternative Splicing". Molecular and Cellular Biology. 29 (6): 1442–1451. doi:10.1128/MCB.01689-08. ISSN 1098-5549. PMC 2648227. PMID 19124611.
  18. ^ Sureau, A. (2001-04-02). "SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs". The EMBO Journal. 20 (7): 1785–1796. doi:10.1093/emboj/20.7.1785. PMC 145484. PMID 11285241.
  19. ^ Campagne, Sébastien; Jutzi, Daniel; Malard, Florian; Matoga, Maja; Romane, Ksenija; Feldmuller, Miki; Colombo, Martino; Ruepp, Marc-David; Allain, Frédéric H-T. (2023-09-04). "Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39". Nature Communications. 14 (1): 5366. Bibcode:2023NatCo..14.5366C. doi:10.1038/s41467-023-40254-5. ISSN 2041-1723. PMC 10477243. PMID 37666821.
  20. ^ Yang, Sisi; Jia, Rong; Bian, Zhuan (September 2018). "SRSF5 functions as a novel oncogenic splicing factor and is upregulated by oncogene SRSF3 in oral squamous cell carcinoma". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1865 (9): 1161–1172. doi:10.1016/j.bbamcr.2018.05.017. PMID 29857020.
  21. ^ Änkö, Minna-Liisa; Müller-McNicoll, Michaela; Brandl, Holger; Curk, Tomaz; Gorup, Crtomir; Henry, Ian; Ule, Jernej; Neugebauer, Karla M (2012-03-21). "The RNA-binding landscapes of two SR proteins reveal unique functions and binding to diverse RNA classes". Genome Biology. 13 (3): R17. doi:10.1186/gb-2012-13-3-r17. ISSN 1474-760X. PMC 3439968. PMID 22436691.
  22. ^ Best, Andrew; James, Katherine; Dalgliesh, Caroline; Hong, Elaine; Kheirolahi-Kouhestani, Mahsa; Curk, Tomaz; Xu, Yaobo; Danilenko, Marina; Hussain, Rafiq; Keavney, Bernard; Wipat, Anil; Klinck, Roscoe; Cowell, Ian G.; Cheong Lee, Ka; Austin, Caroline A. (2014-09-11). "Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons". Nature Communications. 5 (1): 4760. Bibcode:2014NatCo...5.4760B. doi:10.1038/ncomms5760. ISSN 2041-1723. PMC 4175592. PMID 25208576.
  23. ^ Pimentel, Harold; Parra, Marilyn; Gee, Sherry; Ghanem, Dana; An, Xiuli; Li, Jie; Mohandas, Narla; Pachter, Lior; Conboy, John G. (2014-01-17). "A dynamic alternative splicing program regulates gene expression during terminal erythropoiesis". Nucleic Acids Research. 42 (6): 4031–4042. doi:10.1093/nar/gkt1388. PMC 3973340. PMID 24442673.
  24. ^ a b c d e Leclair, Nathan K.; Brugiolo, Mattia; Urbanski, Laura; Lawson, Shane C.; Thakar, Ketan; Yurieva, Marina; George, Joshy; Hinson, John Travis; Cheng, Albert; Graveley, Brenton R.; Anczuków, Olga (November 2020). "Poison Exon Splicing Regulates a Coordinated Network of SR Protein Expression during Differentiation and Tumorigenesis". Molecular Cell. 80 (4): 648–665.e9. doi:10.1016/j.molcel.2020.10.019. PMC 7680420. PMID 33176162.
  25. ^ a b Zhang, Xiaochang; Chen, Ming Hui; Wu, Xuebing; Kodani, Andrew; Fan, Jean; Doan, Ryan; Ozawa, Manabu; Ma, Jacqueline; Yoshida, Nobuaki; Reiter, Jeremy F.; Black, Douglas L.; Kharchenko, Peter V.; Sharp, Phillip A.; Walsh, Christopher A. (2025-08-20). "Cell Type-specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex". Cell. 166 (5): 1147–1162.e15. doi:10.1016/j.cell.2016.07.025. hdl:1721.1/116859. PMC 5248659. PMID 27565344.
  26. ^ de Oliveira Freitas Machado, Camila; Schafranek, Michal; Brüggemann, Mirko; Hernández Cañás, María Clara; Keller, Mario; Di Liddo, Antonella; Brezski, Andre; Blümel, Nicole; Arnold, Benjamin; Bremm, Anja; Wittig, Ilka; Jaé, Nicolas; McNicoll, François; Dimmeler, Stefanie; Zarnack, Kathi (2023-01-25). "Poison cassette exon splicing of SRSF6 regulates nuclear speckle dispersal and the response to hypoxia". Nucleic Acids Research. 51 (2): 870–890. doi:10.1093/nar/gkac1225. ISSN 0305-1048. PMC 9881134. PMID 36620874.
  27. ^ a b Thomas, James D.; Polaski, Jacob T.; Feng, Qing; De Neef, Emma J.; Hoppe, Emma R.; McSharry, Maria V.; Pangallo, Joseph; Gabel, Austin M.; Belleville, Andrea E.; Watson, Jacqueline; Nkinsi, Naomi T.; Berger, Alice H.; Bradley, Robert K. (January 2020). "RNA isoform screens uncover the essentiality and tumor-suppressor activity of ultraconserved poison exons". Nature Genetics. 52 (1): 84–94. doi:10.1038/s41588-019-0555-z. ISSN 1546-1718. PMC 6962552. PMID 31911676.
  28. ^ Karginov, Timofey A.; Ménoret, Antoine; Leclair, Nathan K.; Harrison, Andrew G.; Chandiran, Karthik; Suarez-Ramirez, Jenny E.; Yurieva, Marina; Karlinsey, Keaton; Wang, Penghua; O'Neill, Rachel J.; Murphy, Patrick A.; Adler, Adam J.; Cauley, Linda S.; Anczuków, Olga; Zhou, Beiyan (2024-09-13). "Autoregulated splicing of TRA2 β programs T cell fate in response to antigen-receptor stimulation". Science. 385 (6714): eadj1979. Bibcode:2024Sci...385j1979K. doi:10.1126/science.adj1979. ISSN 0036-8075. PMID 39265028.
  29. ^ Jin, Qi; Harris, Ethan; Myers, Jacquelyn A.; Mehmood, Rashid; Cotton, Anitria; Shirnekhi, Hazheen K.; Baggett, David W.; Wen, Jeremy Qiang; Schild, Andrew B.; Bhansali, Rahul S.; Klein, Jonathon; Narina, Shilpa; Pieters, Tim; Yoshimi, Akihide; Pruett-Miller, Shondra M. (2024-12-05). "Disruption of cotranscriptional splicing suggests RBM39 is a therapeutic target in acute lymphoblastic leukemia". Blood. 144 (23): 2417–2431. doi:10.1182/blood.2024024281. ISSN 0006-4971. PMC 11628860. PMID 39316649.
  30. ^ Vital, Tamara; Wali, Aminah; Butler, Kyle V.; Xiong, Yan; Foster, Joseph P.; Marcel, Shelsa S.; McFadden, Andrew W.; Nguyen, Valerie U.; Bailey, Benton M.; Lamb, Kelsey N.; James, Lindsey I.; Frye, Stephen V.; Mosely, Amber L.; Jin, Jian; Pattenden, Samantha G. (2023-01-30). "MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing". Frontiers in Oncology. 13. doi:10.3389/fonc.2023.1099550. ISSN 2234-943X. PMC 9924231. PMID 36793594.
  31. ^ Kim, Eunhee; Ilagan, Janine O.; Liang, Yang; Daubner, Gerrit M.; Lee, Stanley C.-W.; Ramakrishnan, Aravind; Li, Yue; Chung, Young Rock; Micol, Jean-Baptiste; Murphy, Michele E.; Cho, Hana; Kim, Min-Kyung; Zebari, Ahmad S.; Aumann, Shlomzion; Park, Christopher Y. (May 2015). "SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition". Cancer Cell. 27 (5): 617–630. doi:10.1016/j.ccell.2015.04.006. PMC 4429920. PMID 25965569.
  32. ^ Eom, Taesun; Zhang, Chaolin; Wang, Huidong; Lay, Kenneth; Fak, John; Noebels, Jeffrey L; Darnell, Robert B (2013-01-22). "NOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure". eLife. 2: e00178. doi:10.7554/eLife.00178. ISSN 2050-084X. PMC 3552424. PMID 23359859.
  33. ^ Tan, Zhi-Wei; Fei, George; Paulo, Joao A; Bellaousov, Stanislav; Martin, Sara E S; Duveau, Damien Y; Thomas, Craig J; Gygi, Steven P; Boutz, Paul L; Walker, Suzanne (2020-06-04). "O-GlcNAc regulates gene expression by controlling detained intron splicing". Nucleic Acids Research. 48 (10): 5656–5669. doi:10.1093/nar/gkaa263. ISSN 0305-1048. PMC 7261177. PMID 32329777.
  34. ^ Cheng, Steven S.; Mody, Alison C.; Woo, Christina M. (2024-11-07). "Opportunities for Therapeutic Modulation of O-GlcNAc". Chemical Reviews. 124 (22): 12918–13019. doi:10.1021/acs.chemrev.4c00417. ISSN 0009-2665. PMID 39509538.
  35. ^ Harada, Naoya; Asada, Shuhei; Jiang, Lige; Nguyen, Huy; Moreau, Lisa; Marina, Ryan J.; Adelman, Karen; Iyer, Divya R.; D'Andrea, Alan D. (July 2024). "The splicing factor CCAR1 regulates the Fanconi anemia/BRCA pathway". Molecular Cell. 84 (14): 2618–2633.e10. doi:10.1016/j.molcel.2024.06.031. PMC 11321822. PMID 39025073.
  36. ^ a b Inoue, Daichi; Chew, Guo-Liang; Liu, Bo; Michel, Brittany C.; Pangallo, Joseph; D'Avino, Andrew R.; Hitchman, Tyler; North, Khrystyna; Lee, Stanley Chun-Wei; Bitner, Lillian; Block, Ariele; Moore, Amanda R.; Yoshimi, Akihide; Escobar-Hoyos, Luisa; Cho, Hana (2019-10-09). "Spliceosomal disruption of the non-canonical BAF complex in cancer". Nature. 574 (7778): 432–436. Bibcode:2019Natur.574..432I. doi:10.1038/s41586-019-1646-9. PMC 6858563. PMID 31597964.
  37. ^ Jin, Peng; Wang, Xiaoling; Jin, Qiqi; Zhang, Yi; Shen, Jie; Jiang, Ge; Zhu, Hongming; Zhao, Ming; Wang, Dan; Li, Zeyi; Zhou, Yan; Li, Wenzhu; Zhang, Wei; Liu, Yabin; Wang, Siyang (2024-05-15). "Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia". Cancer Research. 84 (10): 1583–1596. doi:10.1158/0008-5472.CAN-23-2543. ISSN 0008-5472. PMID 38417135.
  38. ^ Zhou, Yalu; Han, Cuijuan; Wang, Eric; Lorch, Adam H.; Serafin, Valentina; Cho, Byoung-Kyu; Diaz, Blanca T. Gutierrez; Calvo, Julien; Fang, Celestia; Khodadadi-Jamayran, Alireza; Tabaglio, Tommaso; Marier, Christian; Kuchmiy, Anna; Sun, Limin; Yacu, George (2022-05-20). "Posttranslational regulation of the exon skipping machinery controls aberrant splicing in leukemia". Cancer Discovery. 10 (9): 1388–1409. doi:10.1158/2159-8290.CD-19-1436. PMC 7483384. PMID 32444465.
  39. ^ Torres-Diz, Manuel; Reglero, Clara; Falkenstein, Catherine D.; Castro, Annette; Hayer, Katharina E.; Radens, Caleb M.; Quesnel-Vallières, Mathieu; Ang, Zhiwei; Sehgal, Priyanka; Li, Marilyn M.; Barash, Yoseph; Tasian, Sarah K.; Ferrando, Adolfo; Thomas-Tikhonenko, Andrei (2024-10-15). "An Alternatively Spliced Gain-of-Function NT5C2 Isoform Contributes to Chemoresistance in Acute Lymphoblastic Leukemia". Cancer Research. 84 (20): 3327–3336. doi:10.1158/0008-5472.CAN-23-3804. ISSN 0008-5472. PMC 11474164. PMID 39094066.
  40. ^ a b Carvill, Gemma L.; Engel, Krysta L.; Ramamurthy, Aishwarya; Cochran, J. Nicholas; Roovers, Jolien; Stamberger, Hannah; Lim, Nicholas; Schneider, Amy L.; Hollingsworth, Georgie; Holder, Dylan H.; Regan, Brigid M.; Lawlor, James; Lagae, Lieven; Ceulemans, Berten; Bebin, E. Martina (December 2018). "Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies". The American Journal of Human Genetics. 103 (6): 1022–1029. doi:10.1016/j.ajhg.2018.10.023. PMC 6288405. PMID 30526861.
  41. ^ a b Voskobiynyk, Yuliya; Battu, Gopal; Felker, Stephanie A.; Cochran, J. Nicholas; Newton, Megan P.; Lambert, Laura J.; Kesterson, Robert A.; Myers, Richard M.; Cooper, Gregory M.; Roberson, Erik D.; Barsh, Gregory S. (2021-01-07). Shieh, Joseph (ed.). "Aberrant regulation of a poison exon caused by a non-coding variant in a mouse model of Scn1a-associated epileptic encephalopathy". PLOS Genetics. 17 (1): e1009195. doi:10.1371/journal.pgen.1009195. ISSN 1553-7404. PMC 7790302. PMID 33411788.
  42. ^ Newman, Jeremy R. B.; Long, S. Alice; Speake, Cate; Greenbaum, Carla J.; Cerosaletti, Karen; Rich, Stephen S.; Onengut-Gumuscu, Suna; McIntyre, Lauren M.; Buckner, Jane H.; Concannon, Patrick (2023-09-27). "Shifts in isoform usage underlie transcriptional differences in regulatory T cells in type 1 diabetes". Communications Biology. 6 (1): 988. doi:10.1038/s42003-023-05327-7. ISSN 2399-3642. PMC 10533491. PMID 37758901.
  43. ^ Kim, Eunhee; Ilagan, Janine O.; Liang, Yang; Daubner, Gerrit M.; Lee, Stanley C.-W.; Ramakrishnan, Aravind; Li, Yue; Chung, Young Rock; Micol, Jean-Baptiste; Murphy, Michele E.; Cho, Hana; Kim, Min-Kyung; Zebari, Ahmad S.; Aumann, Shlomzion; Park, Christopher Y. (May 2015). "SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition". Cancer Cell. 27 (5): 617–630. doi:10.1016/j.ccell.2015.04.006. PMC 4429920. PMID 25965569.
  44. ^ Goodwin, Sara; McPherson, John D.; McCombie, W. Richard (2016-05-17). "Coming of age: ten years of next-generation sequencing technologies". Nature Reviews. Genetics. 17 (6): 333–351. doi:10.1038/nrg.2016.49. ISSN 1471-0064. PMC 10373632. PMID 27184599.
  45. ^ Katsanis, Sara Huston; Katsanis, Nicholas (June 2013). "Molecular genetic testing and the future of clinical genomics". Nature Reviews Genetics. 14 (6): 415–426. doi:10.1038/nrg3493. ISSN 1471-0056. PMC 4461364. PMID 23681062.
  46. ^ Felker, Stephanie A.; Lawlor, James M.J.; Hiatt, Susan M.; Thompson, Michelle L.; Latner, Donald R.; Finnila, Candice R.; Bowling, Kevin M.; Bonnstetter, Zachary T.; Bonini, Katherine E.; Kelly, Nicole R.; Kelley, Whitley V.; Hurst, Anna C.E.; Rashid, Salman; Kelly, Melissa A.; Nakouzi, Ghunwa (August 2023). "Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing". Genetics in Medicine. 25 (8): 100884. doi:10.1016/j.gim.2023.100884. PMC 10524927. PMID 37161864.
  47. ^ Lynch, Danielle C.; Revil, Timothée; Schwartzentruber, Jeremy; Bhoj, Elizabeth J.; Innes, A. Micheil; Lamont, Ryan E.; Lemire, Edmond G.; Chodirker, Bernard N.; Taylor, Juliet P.; Zackai, Elaine H.; McLeod, D. Ross; Kirk, Edwin P.; Hoover-Fong, Julie; Fleming, Leah; Savarirayan, Ravi (2014-07-22). "Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome". Nature Communications. 5 (1): 4483. Bibcode:2014NatCo...5.4483.. doi:10.1038/ncomms5483. ISSN 2041-1723. PMC 4109005. PMID 25047197.
  48. ^ Sheridan, Cormac (2024-08-01). "A new class of mRNA drugs targets poison exons". Nature Biotechnology. 42 (8): 1159–1161. doi:10.1038/s41587-024-02355-4. ISSN 1546-1696. PMID 39143167.
  49. ^ a b c Prajapati, Sudeep; Cameron, Michael; Dunyak, Bryan M.; Shan, Mengge; Siu, Y. Amy; Levin-Furtney, Samantha; Powe, Joshua; Burchfiel, Eileen T.M.; Cabral, Sarah E.; Harney, Alycen M.; Keenan, Regina K.; Larpenteur, Kevin M.; Maag, Jesper L.V.; Snyder, Andrew R.; Nguyen, Dan T. (2023-11-02). "REM-422, a Potent, Selective, Oral Small Molecule mRNA Degrader of the MYB Oncogene, Demonstrates Anti-Tumor Activity in Mouse Xenograft Models of AML". Blood. 142 (Supplement 1): 1425. doi:10.1182/blood-2023-182676. ISSN 0006-4971.
  50. ^ a b Bhattacharyya, Anuradha; Trotta, Christopher R.; Narasimhan, Jana; Wiedinger, Kari J.; Li, Wencheng; Effenberger, Kerstin A.; Woll, Matthew G.; Jani, Minakshi B.; Risher, Nicole; Yeh, Shirley; Cheng, Yaofeng; Sydorenko, Nadiya; Moon, Young-Choon; Karp, Gary M.; Weetall, Marla (2021-12-15). "Small molecule splicing modifiers with systemic HTT-lowering activity". Nature Communications. 12 (1): 7299. Bibcode:2021NatCo..12.7299B. doi:10.1038/s41467-021-27157-z. ISSN 2041-1723. PMC 8674292. PMID 34911927.
  51. ^ a b c Lim, Kian Huat; Han, Zhou; Jeon, Hyun Yong; Kach, Jacob; Jing, Enxuan; Weyn-Vanhentenryck, Sebastien; Downs, Mikaela; Corrionero, Anna; Oh, Raymond; Scharner, Juergen; Venkatesh, Aditya; Ji, Sophina; Liau, Gene; Ticho, Barry; Nash, Huw (2020-07-09). "Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression". Nature Communications. 11 (1): 3501. Bibcode:2020NatCo..11.3501L. doi:10.1038/s41467-020-17093-9. ISSN 2041-1723. PMC 7347940. PMID 32647108.
  52. ^ Campagne, Sébastien; Boigner, Sarah; Rüdisser, Simon; Moursy, Ahmed; Gillioz, Laurent; Knörlein, Anna; Hall, Jonathan; Ratni, Hasane; Cléry, Antoine; Allain, Frédéric H.-T. (December 2019). "Structural basis of a small molecule targeting RNA for a specific splicing correction". Nature Chemical Biology. 15 (12): 1191–1198. doi:10.1038/s41589-019-0384-5. ISSN 1552-4450. PMC 7617061. PMID 31636429.
  53. ^ a b Preußner, Marco; Smith, Heather L; Hughes, Daniel; Zhang, Min; Emmerichs, Ann-Kathrin; Scalzitti, Silvia; Peretti, Diego; Swinden, Dean; Neumann, Alexander; Haltenhof, Tom; Mallucci, Giovanna R; Heyd, Florian (2023-05-08). "ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo". EMBO Molecular Medicine. 15 (5): e17157. doi:10.15252/emmm.202217157. ISSN 1757-4676. PMC 10165353. PMID 36946385.
  54. ^ a b Havens, Mallory A.; Hastings, Michelle L. (2016-06-10). "Splice-switching antisense oligonucleotides as therapeutic drugs". Nucleic Acids Research. 44 (14): 6549–6563. doi:10.1093/nar/gkw533. PMC 5001604. PMID 27288447.
  55. ^ Isom, Lori L.; Knupp, Kelly G. (July 2021). "Dravet Syndrome: Novel Approaches for the Most Common Genetic Epilepsy". Neurotherapeutics. 18 (3): 1524–1534. doi:10.1007/s13311-021-01095-6. PMC 8608987. PMID 34378168.
  56. ^ Han, Zhou; Chen, Chunling; Christiansen, Anne; Ji, Sophina; Lin, Qian; Anumonwo, Charles; Liu, Chante; Leiser, Steven C.; Meena; Aznarez, Isabel; Liau, Gene; Isom, Lori L. (2020-08-26). "Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome". Science Translational Medicine. 12 (558). doi:10.1126/scitranslmed.aaz6100. ISSN 1946-6234. PMID 32848094.
  57. ^ Wengert, Eric R.; Wagley, Pravin K.; Strohm, Samantha M.; Reza, Nuha; Wenker, Ian C.; Gaykema, Ronald P.; Christiansen, Anne; Liau, Gene; Patel, Manoj K. (January 2022). "Targeted Augmentation of Nuclear Gene Output (TANGO) of Scn1a rescues parvalbumin interneuron excitability and reduces seizures in a mouse model of Dravet Syndrome". Brain Research. 1775: 147743. doi:10.1016/j.brainres.2021.147743. PMID 34843701.
  58. ^ "An Open-Label Extension Study of STK-001 for Patients With Dravet Syndrome". 7 May 2024.
  59. ^ "Stoke Therapeutics Receives FDA Breakthrough Therapy Designation for Zorevunersen for the Treatment of Dravet Syndrome".
  60. ^ "Stoke Therapeutics Presents New Open-Label Extension (OLE) Study Data That Further Support the Potential for Zorevunersen as a Disease-Modifying Medicine for the Treatment of Dravet Syndrome".
  61. ^ Feuerstein, Adam. "Why Stoke Therapeutics' Dravet syndrome drug is worth watching". STAT.
  62. ^ Venkatesh, Aditya; McKenty, Taylor; Ali, Syed; Sonntag, Donna; Ravipaty, Shobha; Cui, Yanyan; Slate, Deirdre; Lin, Qian; Christiansen, Anne; Jacobson, Sarah; Kach, Jacob; Lim, Kian Huat; Srinivasan, Vaishnavi; Zinshteyn, Boris; Aznarez, Isabel (2024-10-01). "Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells". Nucleic Acid Therapeutics. 34 (5): 221–233. doi:10.1089/nat.2024.0022. ISSN 2159-3337. PMC 11564677. PMID 39264859.
  63. ^ "Study of REM-422 in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma". 19 November 2024.
  64. ^ "Study of REM-422 in Patients With AML or Higher Risk MDS". 19 November 2024.
  65. ^ Naryshkin, Nikolai A.; Weetall, Marla; Dakka, Amal; Narasimhan, Jana; Zhao, Xin; Feng, Zhihua; Ling, Karen K. Y.; Karp, Gary M.; Qi, Hongyan; Woll, Matthew G.; Chen, Guangming; Zhang, Nanjing; Gabbeta, Vijayalakshmi; Vazirani, Priya; Bhattacharyya, Anuradha (2014-08-08). "SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy". Science. 345 (6197): 688–693. Bibcode:2014Sci...345..688N. doi:10.1126/science.1250127. ISSN 0036-8075. PMID 25104390.
  66. ^ Ratni, Hasane; Ebeling, Martin; Baird, John; Bendels, Stefanie; Bylund, Johan; Chen, Karen S.; Denk, Nora; Feng, Zhihua; Green, Luke; Guerard, Melanie; Jablonski, Philippe; Jacobsen, Bjoern; Khwaja, Omar; Kletzl, Heidemarie; Ko, Chien-Ping (2018-08-09). "Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2 ) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)". Journal of Medicinal Chemistry. 61 (15): 6501–6517. doi:10.1021/acs.jmedchem.8b00741. ISSN 0022-2623. PMID 30044619.
  67. ^ Fair, Benjamin; Buen Abad Najar, Carlos F.; Zhao, Junxing; Lozano, Stephanie; Reilly, Austin; Mossian, Gabriela; Staley, Jonathan P.; Wang, Jingxin; Li, Yang I. (September 2024). "Global impact of unproductive splicing on human gene expression". Nature Genetics. 56 (9): 1851–1861. doi:10.1038/s41588-024-01872-x. ISSN 1546-1718. PMC 11387194. PMID 39223315.
  68. ^ Xi, Simon; Soulard, Patricia; Li, Kai; Gu, Xiubin; Kay, Ibrahim; Hasson, Sam; Yates, Chris; Sadlish, Heather; Lee, Jay; Weng, Zhiping; Xu, Simon; Wager, Travis (2024-06-01). "Effect of RGT-61159 on inhibition of oncogene c-MYB synthesis and tumor growth inhibition in a broad range of ACC PDX models, at well tolerated doses in rodents and non-human primates". Journal of Clinical Oncology. 42 (16_suppl): 6107. doi:10.1200/JCO.2024.42.16_suppl.6107. ISSN 0732-183X.
  69. ^ "Study of Safety and Efficacy of RGT-61159 in Adults with Relapsed/ Refractory Adenoid Cystic Carcinoma (ACC) or Colorectal Carcinoma (CRC)". 21 November 2024.
  70. ^ Gao, Lan; Bhattacharyya, Anuradha; Beers, Brian; Kaushik, Diksha; Bredlau, Amy-Lee; Kristensen, Allan; Abd-Elaziz, Khalid; Grant, Richard; Golden, Lee; Kong, Ronald (2024-08-18). "Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: A first-in-human study". British Journal of Clinical Pharmacology. 90 (12): 3242–3251. doi:10.1111/bcp.16202. ISSN 0306-5251. PMC 11602954. PMID 39155237.
  71. ^ "A Study to Evaluate the Safety and Efficacy of PTC518 in Participants With Huntington's Disease (HD)". 4 October 2024.
  72. ^ "PTC Therapeutics Enters into a Global License and Collaboration Agreement with Novartis for PTC518 Huntington's Disease Program" (Press release). December 2, 2024.
  73. ^ Yang, Runwei; Feng, Xinran; Arias-Cavieres, Alejandra; Mitchell, Robin M.; Polo, Ashleigh; Hu, Kaining; Zhong, Rong; Qi, Cai; Zhang, Rachel S.; Westneat, Nathaniel; Portillo, Cristabel A.; Nobrega, Marcelo A.; Hansel, Christian; Garcia III, Alfredo J.; Zhang, Xiaochang (May 2023). "Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing". Neuron. 111 (10): 1637–1650.e5. doi:10.1016/j.neuron.2023.02.021. PMC 10198817. PMID 36917980.
  74. ^ Kim, Young Jin; Sivetz, Nicole; Layne, Jessica; Voss, Dillon M.; Yang, Lucia; Zhang, Qian; Krainer, Adrian R. (2022-01-18). "Exon-skipping antisense oligonucleotides for cystic fibrosis therapy". Proceedings of the National Academy of Sciences. 119 (3). Bibcode:2022PNAS..11914858K. doi:10.1073/pnas.2114858118. ISSN 0027-8424. PMC 8784140. PMID 35017301.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Poison_exon&oldid=1264067650"