Trans-splicing

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The joining of parts of different RNAs is called trans-splicing . In contrast to normal cis- splicing , parts of different RNAs that can come from the same gene are linked with one another. The “classic” trans-splicing occurs in trypanosomes and nematodes , and some cases of trans-splicing in humans have also been discovered.

“Classic” trans-splicing in trypanosomes and nematodes

Overview of the processing of pre-mRNA in trypanosomes. In addition to cis-splicing (only one known intron , see text), trans-splicing occurs here, in which either a so-called mini-exon of the spliced ​​leader RNA (SL-RNA) (shown as a gray box) is linked to an exon of a polycistronic transcript (colored boxes) or two pre-mRNAs are combined. So here two different RNAs are spliced ​​"in trans", which gives the whole process its name. Finally, the polyadenylation releases the finished mRNA with the poly (A) tail (shown as A (n)).

Kinetoplastida , which include the pathogens of sleeping sickness, Chagas disease and Nagana, in particular Trypanosoma brucei brucei , are the classic model organisms for trans-splicing in the narrower sense. During transcription, these organisms produce a polycistronic transcript , similar to bacteria , from which individual genes are released by trans-splicing. This reaction takes place in a special type of spliceosome in which the U1 snRNP is replaced by the so-called “spliced ​​leader” (SL) snRNP. Unlike the U1 snRNA , however, the spliced ​​leader RNA is consumed in the splicing reaction, since its 5 'end contains a miniexon which, together with the exon of the polycistronic transcript, later makes up the mRNA (see figure on the right). The miniexon of the SL-RNA also contains the AUG start codon, so it is essential for a complete mRNA with a correct open reading frame .

In addition to the trans-splicing, only a single “classic” cis-intron was discovered in the gene for the poly-A-polymerase in trypanosomes, which means that trypanosomes also contain a U1-snRNP, but only in extremely small quantities (this was also recently characterized).

Trans-splicing in the narrower sense has also been observed in nematodes and Ciona intestinalis , but is absent in many other organisms.

Trans-splicing in humans

Some cases of trans splicing have also been reported in humans. In contrast to trypanosomes, however, there is no spliced ​​leader snRNP, i.e. no trans-splicing in the “classic” sense. Rather, two pre-mRNAs of the same gene are processed with one another, which in all cases reported so far do not differ from one another in their sequence (hence also trans-splicing, because two independent RNAs are spliced ​​together). This results in a duplication of an exon in the later mRNA. However, this process rarely occurs in humans (current figures speak of two "real" examples that can only be found with 15 ESTs in the databases), but the reports sparked a heated discussion as to whether this process was not exploited Ways could be found to treat hereditary diseases (initial efforts have already been made with the Tau gene, which plays a role in dementias such as Alzheimer's disease ). Here too, however, there is the problem of the delivery of the 'active ingredient', which in this case represents an RNA - as is the case with a large number of other innovative, but also long-known therapeutic strategies .

Trans-splicing also plays a role in cyanobacteria (see article Intein , last paragraph).

Applications

Trans-splicing is being studied to treat genetic defects without gene therapy by correcting the mRNA.

literature

Individual evidence

  1. a b E. L. Lasda, T. Blumenthal: Trans-splicing. In: Wiley interdisciplinary reviews. RNA. Volume 2, Number 3, 2011 May-Jun, pp. 417-434, ISSN  1757-7012 . doi : 10.1002 / wrna.71 . PMID 21957027 .
  2. T. Horiuchi, T. Aigaki: Alternative trans-splicing: a novel mode of pre-mRNA processing. In: Biology of the cell / under the auspices of the European Cell Biology Organization. Volume 98, Number 2, February 2006, pp. 135-140, ISSN  0248-4900 . doi : 10.1042 / BC20050002 . PMID 16417469 .
  3. T. Blumenthal: Trans-splicing and operons. In: WormBook: the online review of C. elegans biology. 2005, pp. 1-9, ISSN  1551-8507 . doi : 10.1895 / wormbook.1.5.1 . PMID 18050426 .
  4. RH Herai, ME Yamagishi: Detection of human interchromosomal trans-splicing in sequence data banks. In: Briefings in bioinformatics. Volume 11, Number 2, March 2010, pp. 198-209, ISSN  1477-4054 . doi : 10.1093 / bib / bbp041 . PMID 19955235 .
  5. T. Fiskaa, AB Birgisdottir: RNA reprogramming and repair based on trans-splicing group I ribozymes. In: New biotechnology. Volume 27, Number 3, July 2010, pp. 194-203, ISSN  1876-4347 . doi : 10.1016 / j.nbt.2010.02.013 . PMID 20219714 .
  6. ^ V. Wally, EM Murauer, JW Bauer: Spliceosome-mediated trans-splicing: the therapeutic cut and paste. In: Journal of Investigative Dermatology . Volume 132, Number 8, August 2012, pp. 1959-1966, ISSN  1523-1747 . doi : 10.1038 / jid.2012.101 . PMID 22495179 .