trans splicing


Summary: The joining of RNA from two different genes. One type of trans-splicing is the "spliced leader" type (primarily found in protozoans such as trypanosomes and in lower invertebrates such as nematodes) which results in the addition of a capped, noncoding, spliced leader sequence to the 5' end of mRNAs. Another type of trans-splicing is the "discontinuous group II introns" type (found in plant/algal chloroplasts and plant mitochondria) which results in the joining of two independently transcribed coding sequences. Both are mechanistically similar to conventional nuclear pre-mRNA cis-splicing. Mammalian cells are also capable of trans-splicing.

Top Publications

  1. Vandenberghe A, Meedel T, Hastings K. mRNA 5'-leader trans-splicing in the chordates. Genes Dev. 2001;15:294-303 pubmed
    ..SL trans-splicing is not known to occur in the vertebrates. However, because ascidians are primitive chordates related to vertebrate ancestors, our findings raise the possibility of ancestral SL trans-splicing in the vertebrate lineage. ..
  2. Groth Malonek M, Pruchner D, Grewe F, Knoop V. Ancestors of trans-splicing mitochondrial introns support serial sister group relationships of hornworts and mosses with vascular plants. Mol Biol Evol. 2005;22:117-25 pubmed
  3. Liu Y, Huang T, MacMorris M, Blumenthal T. Interplay between AAUAAA and the trans-splice site in processing of a Caenorhabditis elegans operon pre-mRNA. RNA. 2001;7:176-81 pubmed
    ..elegans; (2) the AAUAAA is important in determining SL2 trans-splicing events more than 100 bp downstream; and (3) in some circumstances, 3' end formation may occur by a trans-splicing-dependent mechanism. ..
  4. Coady T, Baughan T, Shababi M, Passini M, Lorson C. Development of a single vector system that enhances trans-splicing of SMN2 transcripts. PLoS ONE. 2008;3:e3468 pubmed publisher
    ..These results demonstrate that the ASO-tsRNA strategy provides insight into the trans-splicing mechanism and a means of significantly enhancing trans-splicing activity in vivo. ..
  5. Hastings K. SL trans-splicing: easy come or easy go?. Trends Genet. 2005;21:240-7 pubmed
    ..In this article, I summarize the evolutionarily relevant aspects of SL trans-splicing and consider the interplay among SL trans-splicing, pre-mRNA splice-signal syntax and evolutionary genomics. ..
  6. Blumenthal T, Evans D, Link C, Guffanti A, Lawson D, Thierry Mieg J, et al. A global analysis of Caenorhabditis elegans operons. Nature. 2002;417:851-4 pubmed
    ..elegans genes. Numerous examples of co-transcription of genes encoding functionally related proteins are evident. Inspection of the operon list should reveal previously unknown functional relationships. ..
  7. Belhocine K, Mak A, Cousineau B. Trans-splicing versatility of the Ll.LtrB group II intron. RNA. 2008;14:1782-90 pubmed publisher
    ..This work unveils the great versatility of group II intron fragments to assemble and accurately trans-splice their flanking exons in vivo. ..
  8. Dorn R, Krauss V. The modifier of mdg4 locus in Drosophila: functional complexity is resolved by trans splicing. Genetica. 2003;117:165-77 pubmed
    ..the fact that some mod(mdg4) transcripts are encoded by both antiparallel DNA strands, it was shown that mRNA trans splicing is the mechanism used by this locus to produce mature transcripts...
  9. Liu C, de Oliveira A, Higazi T, Ghedin E, DePasse J, Unnasch T. Sequences necessary for trans-splicing in transiently transfected Brugia malayi. Mol Biochem Parasitol. 2007;156:62-73 pubmed
    ..malayi genes found homologues for the BmHSP70 TSM in roughly 25%. Thus, while the BmHSP70 TSM is necessary and sufficient to direct trans-splicing in some genomic contexts, independent trans-splicing signals are employed by other genes...

Scientific Experts

More Information


  1. Jäger A, De Gaudenzi J, Cassola A, D ORSO I, Frasch A. mRNA maturation by two-step trans-splicing/polyadenylation processing in trypanosomes. Proc Natl Acad Sci U S A. 2007;104:2035-42 pubmed
    ..We propose that splice-site skipping might be part of a posttranscriptional mechanism to regulate gene expression in trypanosomes, through the generation of premature nontranslatable RNA molecules. ..
  2. Zayed H, Xia L, Yerich A, Yant S, Kay M, Puttaraju M, et al. Correction of DNA protein kinase deficiency by spliceosome-mediated RNA trans-splicing and sleeping beauty transposon delivery. Mol Ther. 2007;15:1273-9 pubmed
    ..These results suggest that SB-based trans-splicing vectors should prove useful in facilitating the correction of endogenous mutated mRNA transcripts, including the DNA-PKcs defect present in SCID cells. ..
  3. Lidie K, Van Dolah F. Spliced leader RNA-mediated trans-splicing in a dinoflagellate, Karenia brevis. J Eukaryot Microbiol. 2007;54:427-35 pubmed
    ..brevis occurs via a trans-splicing process in which a common SL sequence is added to the 5'-end of mature mRNAs. The occurrence of SL trans-splicing in a dinoflagellate extends the known phylogenetic range of this process. ..
  4. Li H, Tschudi C. Novel and essential subunits in the 300-kilodalton nuclear cap binding complex of Trypanosoma brucei. Mol Cell Biol. 2005;25:2216-26 pubmed publisher
    ..brucei CBC by RNA interference demonstrated an essential function at an early step in trans-splicing. Thus, our studies are consistent with the CBC providing a mechanistic link between cap 4 modifications and trans-splicing...
  5. Balczun C, Bunse A, Hahn D, Bennoun P, Nickelsen J, Kück U. Two adjacent nuclear genes are required for functional complementation of a chloroplast trans-splicing mutant from Chlamydomonas reinhardtii. Plant J. 2005;43:636-48 pubmed
    ..We propose that the two nuclear factors Rat1 and Rat2 are involved in processing of chloroplast tscA RNA and in subsequent splicing of psaA exons 1 and 2. ..
  6. Liang X, Liu Q, Liu L, Tschudi C, Michaeli S. Analysis of spliceosomal complexes in Trypanosoma brucei and silencing of two splicing factors Prp31 and Prp43. Mol Biochem Parasitol. 2006;145:29-39 pubmed
    ..We identified a 45S complex carrying pre-mRNA and all the U-snRNAs, including U1 and the SL RNA, suggesting that a single spliceosomal complex may potentially conduct both trans- and cis-splicing. ..
  7. Coady T, Shababi M, Tullis G, Lorson C. Restoration of SMN function: delivery of a trans-splicing RNA re-directs SMN2 pre-mRNA splicing. Mol Ther. 2007;15:1471-8 pubmed
    ..Together these results demonstrate that the alternatively spliced SMN2 exon 7 is a tractable target for replacement by trans-splicing. ..
  8. Kierlin Duncan M, Sullenger B. Using 5'-PTMs to repair mutant beta-globin transcripts. RNA. 2007;13:1317-27 pubmed
    ..This study reveals desirable characteristics in substrate RNAs for trans-splicing therapeutics as well as provides an opportunity for further exploration into general splicing mechanisms via 5'-PTMs. ..
  9. Graber J, Salisbury J, Hutchins L, Blumenthal T. C. elegans sequences that control trans-splicing and operon pre-mRNA processing. RNA. 2007;13:1409-26 pubmed
  10. Campbell D, Sturm N, Yu M. Transcription of the kinetoplastid spliced leader RNA gene. Parasitol Today. 2000;16:78-82 pubmed
    ..In this article, David Campbell, Nancy Sturm and Michael Yu review the field of kinetoplastid SL RNA gene transcription, address past proposals in light of current data and discuss some of the differences that appear in the literature. ..
  11. Li H, Wang J, Mor G, Sklar J. A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells. Science. 2008;321:1357-61 pubmed publisher
    ..These observations suggest that certain gene fusions may be pro-neoplastic owing to constitutive expression of chimeric gene products normally generated by trans-splicing of RNAs in developing tissues. ..
  12. Chen H, Kathirvel P, Yee W, Lai P. Correction of dystrophia myotonica type 1 pre-mRNA transcripts by artificial trans-splicing. Gene Ther. 2009;16:211-7 pubmed publisher
    ..81 to 7.41%. These findings confirm that artificial trans-splicing can repair DMPK pre-mRNA and provide proof-of-principle evidence for this approach as potential therapeutic strategy for DM1. ..
  13. Gingeras T. Implications of chimaeric non-co-linear transcripts. Nature. 2009;461:206-11 pubmed publisher
    ..The existence of such chimaeric RNAs has far-reaching implications for the potential information content of genomes and the way it is arranged. ..
  14. Herai R, Yamagishi M. Detection of human interchromosomal trans-splicing in sequence databanks. Brief Bioinform. 2010;11:198-209 pubmed publisher
    ..Our methodology can be applied to 5'-UTR, coding sequences and 3'-UTR in order to find new candidates for a posteriori experimental confirmation. ..
  15. Tasic B, Nabholz C, Baldwin K, Kim Y, Rueckert E, Ribich S, et al. Promoter choice determines splice site selection in protocadherin alpha and gamma pre-mRNA splicing. Mol Cell. 2002;10:21-33 pubmed
    ..However, virtually every variable exon can engage in trans-splicing with constant exons from another cluster, albeit at a far lower level. ..
  16. Lee K, Sommer R. Operon structure and trans-splicing in the nematode Pristionchus pacificus. Mol Biol Evol. 2003;20:2097-103 pubmed
    ..pacificus contains operons and that downstream genes are trans-spliced to SL2. Surprisingly, the one operon analyzed so far in P. pacificus is not conserved in C. elegans, suggesting unexpected genomic plasticity. ..
  17. Qiu Y, Palmer J. Many independent origins of trans splicing of a plant mitochondrial group II intron. J Mol Evol. 2004;59:80-9 pubmed
    ..Using a multigene land plant phylogeny, we infer that the intron underwent a transition from cis to trans splicing 15 times among the sampled angiosperms...
  18. Moore R, Lee I, Silverman G, Harrison P, Strome R, Heinrich C, et al. Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel. J Mol Biol. 1999;292:797-817 pubmed
  19. Pouchkina Stantcheva N, Tunnacliffe A. Spliced leader RNA-mediated trans-splicing in phylum Rotifera. Mol Biol Evol. 2005;22:1482-9 pubmed
  20. Zhang C, Xie Y, Martignetti J, Yeo T, Massa S, Longo F. A candidate chimeric mammalian mRNA transcript is derived from distinct chromosomes and is associated with nonconsensus splice junction motifs. DNA Cell Biol. 2003;22:303-15 pubmed
  21. Liang X, Haritan A, Uliel S, Michaeli S. trans and cis splicing in trypanosomatids: mechanism, factors, and regulation. Eukaryot Cell. 2003;2:830-40 pubmed
  22. Bell M, Sinha J, Johnson A, Testa S. Enhancing the second step of the trans excision-splicing reaction of a group I ribozyme by exploiting P9.0 and P10 for intermolecular recognition. Biochemistry. 2004;43:4323-31 pubmed
    ..Both of these inhibitory components can be overcome by utilizing P9.0 and P10 elongated ribozymes. This work sets forth an initial framework for rationally designing more effective trans excision-splicing ribozymes. ..
  23. Liu Y, Kuersten S, Huang T, Larsen A, MacMorris M, Blumenthal T. An uncapped RNA suggests a model for Caenorhabditis elegans polycistronic pre-mRNA processing. RNA. 2003;9:677-87 pubmed
    ..Our results also demonstrate that MS2 coat protein can be used as an in vivo block to an exonuclease, which should have utility in mRNA stability studies. ..
  24. Dotson P, Sinha J, Testa S. A Pneumocystis carinii group I intron-derived ribozyme utilizes an endogenous guanosine as the first reaction step nucleophile in the trans excision-splicing reaction. Biochemistry. 2008;47:4780-7 pubmed publisher
    ..Unexpectedly, we also found that ribozyme constructs become truncated in vivo, probably through intramolecular 3'-hydrolysis (self-activation), to create functional 3'-terminal nucleotides...
  25. Satou Y, Hamaguchi M, Takeuchi K, Hastings K, Satoh N. Genomic overview of mRNA 5'-leader trans-splicing in the ascidian Ciona intestinalis. Nucleic Acids Res. 2006;34:3378-88 pubmed
    ..An interesting feature of the Ciona polycistronic transcription units is that the great majority entirely lack intercistronic sequences. ..
  26. Arhin G, Ullu E, Tschudi C. 2'-O-methylation of position 2 of the trypanosome spliced leader cap 4 is mediated by a 48 kDa protein related to vaccinia virus VP39. Mol Biochem Parasitol. 2006;147:137-9 pubmed publisher
  27. Rivier C, Goldschmidt Clermont M, Rochaix J. Identification of an RNA-protein complex involved in chloroplast group II intron trans-splicing in Chlamydomonas reinhardtii. EMBO J. 2001;20:1765-73 pubmed
    ..These partners, in association with other factors, form a chloroplast RNP particle that is required for the splicing of the first intron of psaA and which may be the counterpart of eukaryotic snRNPs involved in nuclear splicing. ..
  28. Mitchell L, McGarrity G. Gene therapy progress and prospects: reprograming gene expression by trans-splicing. Gene Ther. 2005;12:1477-85 pubmed
  29. Higazi T, Unnasch T. Intron encoded sequences necessary for trans splicing in transiently transfected Brugia malayi. Mol Biochem Parasitol. 2004;137:181-4 pubmed
  30. Martin D, Xu M, Evans T. Characterization of a naturally occurring trans-splicing intein from Synechocystis sp. PCC6803. Biochemistry. 2001;40:1393-402 pubmed
    ..This work describes an in-depth kinetic analysis of the splicing and cleavage activity of an intein, and provides insight for the use of the split intein as an affinity domain. ..
  31. Helm J, Wilson M, Donelson J. Different trans RNA splicing events in bloodstream and procyclic Trypanosoma brucei. Mol Biochem Parasitol. 2008;159:134-7 pubmed publisher
    ..These alternative SL addition sites may be aberrant or they might be utilized to expand the number of gene products from individual genes. Future experiments on endogenous genes will be necessary to examine the latter possibility. ..
  32. Randau L, Münch R, Hohn M, Jahn D, Soll D. Nanoarchaeum equitans creates functional tRNAs from separate genes for their 5'- and 3'-halves. Nature. 2005;433:537-41 pubmed
    ..As the joining mechanism possibly involves tRNA trans-splicing, the presence of an intron might have been required for early tRNA synthesis...
  33. Li X, Zhao L, Jiang H, Wang W. Short homologous sequences are strongly associated with the generation of chimeric RNAs in eukaryotes. J Mol Evol. 2009;68:56-65 pubmed publisher
    ..In addition to the classical trans-splicing model, we propose a new model, the transcriptional slippage model, to explain the generation of those chimeric RNAs synthesized from templates with SHSs. ..
  34. Stern M, Gupta S, Salmon Divon M, Haham T, Barda O, Levi S, et al. Multiple roles for polypyrimidine tract binding (PTB) proteins in trypanosome RNA metabolism. RNA. 2009;15:648-65 pubmed publisher
    ..The trypanosome PTB proteins, like their mammalian homologs, represent multivalent RNA binding proteins that regulate mRNAs from their synthesis to degradation. ..
  35. Mansfield S, Clark R, Puttaraju M, Kole J, Cohn J, Mitchell L, et al. 5' exon replacement and repair by spliceosome-mediated RNA trans-splicing. RNA. 2003;9:1290-7 pubmed
    ..These studies demonstrate that (1) SMaRT can be used to reprogram the 5' end of mRNA, and (2) efficiency can be improved substantially. ..
  36. Guiliano D, Blaxter M. Operon conservation and the evolution of trans-splicing in the phylum Nematoda. PLoS Genet. 2006;2:e198 pubmed publisher
    ..Mapping these phenotypes onto the robust molecular phylogeny for the Nematoda suggests that operons evolved before SL2-like spliced leaders, which are an evolutionary invention of the rhabditine lineage...
  37. Kwon Y, Coleman M, Camarero J. Selective immobilization of proteins onto solid supports through split-intein-mediated protein trans-splicing. Angew Chem Int Ed Engl. 2006;45:1726-9 pubmed
  38. Lall S, Friedman C, Jankowska Anyszka M, Stepinski J, Darzynkiewicz E, Davis R. Contribution of trans-splicing, 5' -leader length, cap-poly(A) synergism, and initiation factors to nematode translation in an Ascaris suum embryo cell-free system. J Biol Chem. 2004;279:45573-85 pubmed
  39. Sun W, Yang J, Liu X. Synthetic two-piece and three-piece split inteins for protein trans-splicing. J Biol Chem. 2004;279:35281-6 pubmed
    ..We have also demonstrated for the first time that a three-piece split intein could function in protein trans-splicing. These findings have implications for intein structure-function, evolution, and uses in biotechnology. ..
  40. Rodriguez Martin T, Garcia Blanco M, Mansfield S, Grover A, Hutton M, Yu Q, et al. Reprogramming of tau alternative splicing by spliceosome-mediated RNA trans-splicing: implications for tauopathies. Proc Natl Acad Sci U S A. 2005;102:15659-64 pubmed
    ..Our results demonstrate that an alternatively spliced exon can be replaced by trans-splicing and open the way to novel therapeutic applications of SMaRT for tauopathies and other disorders linked to aberrant alternative splicing. ..
  41. Siegel T, Tan K, Cross G. Systematic study of sequence motifs for RNA trans splicing in Trypanosoma brucei. Mol Cell Biol. 2005;25:9586-94 pubmed
    mRNA maturation in Trypanosoma brucei depends upon trans splicing, and variations in trans-splicing efficiency could be an important step in controlling the levels of individual mRNAs...
  42. Mansfield S, Chao H, Walsh C. RNA repair using spliceosome-mediated RNA trans-splicing. Trends Mol Med. 2004;10:263-8 pubmed
  43. Kikumori T, Cote G, Gagel R. Promiscuity of pre-mRNA spliceosome-mediated trans splicing: a problem for gene therapy?. Hum Gene Ther. 2001;12:1429-41 pubmed
    b>Trans splicing of messenger RNA has been used in experimental settings to replace mutant RNA sequences...
  44. Campos P, Bartholomeu D, DaRocha W, Cerqueira G, Teixeira S. Sequences involved in mRNA processing in Trypanosoma cruzi. Int J Parasitol. 2008;38:1383-9 pubmed publisher
  45. Xu M, Evans T. Intein-mediated ligation and cyclization of expressed proteins. Methods. 2001;24:257-77 pubmed
    ..The first two sections of the article provide a brief review of the distinct chemical steps that underlie protein splicing and intein enabled technology. ..
  46. Lai Y, Li D, Yue Y, Duan D. Design of trans-splicing adeno-associated viral vectors for Duchenne muscular dystrophy gene therapy. Methods Mol Biol. 2008;433:259-75 pubmed publisher
    ..We also provide methods to evaluate transduction efficiency of the mini-dystrophin trans-splicing vectors in mdx mouse, a model for DMD. ..
  47. Sierro N, Li S, Suzuki Y, Yamashita R, Nakai K. Spatial and temporal preferences for trans-splicing in Ciona intestinalis revealed by EST-based gene expression analysis. Gene. 2009;430:44-9 pubmed publisher
    ..intestinalis, although there may not exist strong fundamental requirements for genes to be trans-spliced, the populations of non-trans-spliced and trans-spliced genes are likely to be spatially and temporally regulated differently. ..
  48. He Z, Zou H, Wang Y, Zhu J, Yu G. Maturation of the nodule-specific transcript MsHSF1c in Medicago sativa may involve interallelic trans-splicing. Genomics. 2008;92:115-21 pubmed publisher
    ..These results provide new insight into the role of tissue-specific contribution in the transcription of plant HSF genes. ..
  49. Viles K, Sullenger B. Proximity-dependent and proximity-independent trans-splicing in mammalian cells. RNA. 2008;14:1081-94 pubmed publisher
    ..Thus, we find multiple cellular pre-mRNAs require PTM expression in close proximity to trans-splice while others do not. ..
  50. Liu C, Oliveira A, Chauhan C, Ghedin E, Unnasch T. Functional analysis of putative operons in Brugia malayi. Int J Parasitol. 2010;40:63-71 pubmed publisher
  51. Ben Dov C, Levin M, Vazquez M. Analysis of the highly efficient pre-mRNA processing region HX1 of Trypanosoma cruzi. Mol Biochem Parasitol. 2005;140:97-105 pubmed
  52. Pergolizzi R, Crystal R. Genetic medicine at the RNA level: modifications of the genetic repertoire for therapeutic purposes by pre-mRNA trans-splicing. C R Biol. 2004;327:695-709 pubmed
    ..To demonstrate the potential of therapeutic trans-splicing, eukaryotic cis-splicing and trans-splicing are reviewed, followed by a discussion of strategies of therapeutic pre-mRNA trans-splicing directed by exogenous gene transfer. ..
  53. Yin J, Yu L, Savage Dunn C. Alternative trans-splicing of Caenorhabditis elegans sma-9/schnurri generates a short transcript that provides tissue-specific function in BMP signaling. BMC Mol Biol. 2010;11:46 pubmed publisher
    ..The alternative trans-splicing of sma-9 may contribute to the diversity of functions necessary to mediate tissue-specific outputs of BMP signaling. ..