Antisense RNA

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Translation inhibition by antisense RNA

The antisense RNA ( aRNA ), also natural antisense transcript (NAT) called, is a single-stranded RNA that is complementary protein coding for a messenger RNA ( mRNA ) is. The aRNA is assigned to the lncRNAs or ncRNAs. It plays an important role in regulatory processes in cells, but it is also increasingly used in research as a tool for gene knockdown .

structure

The structure of aRNA is naturally similar to that of mRNA. However, almost all aRNAs have secondary structures , such as stem-loops and in some cases also more complex tertiary structures , such as pseudo-knots between these very same secondary structures. These structural elements determine the rate of degradation by intracellular ribonucleases and also the rate at which the aRNA pairs with the complementary RNA.

Action path

The aRNA can act in a number of ways. It mostly works by preventing the translation of a gene. But it can also have an epigenetic or activating effect.

Translation

The mRNA is transcribed from the template strand of the DNA . The non-template strand is thus the codogenic strand. If this - the strand complementary to the template strand - is also transcribed, an aRNA which is complementary to the mRNA is created. By base pairing with the complementary mRNA, the aRNA inhibits its translation in the cell .

An alternative mode of action is the binding of the aRNA to the binding sites of miRNA and the associated stabilization of the RNA. It is believed that this mechanism also plays a role in Alzheimer's disease . Thus the will expression of individual genes regulated .

Epigenetics

It is known that aRNA can also act epigenetically. Longer aRNAs can usually be observed here. This can be caused, for example, by the aRNA-induced methylation of CpG islands in the genome. Such an effect has been demonstrated , for example, in connection with the disease α-thalassemia or the silencing of X chromosomes .

Epigenetic pathways of action of aRNA.

activation

It is also possible that aRNA has an activating effect. This is achieved, for example, in that the aRNA binds to the RNA of a hairpin structure and thus exposes a Shine-Dalgarno sequence hidden in it and thus enables translation.

classification

Antisense RNA can represent both a cis and a trans-acting element. In the first case, the aRNA is transcribed from the complementary DNA strand. So one often has a very high degree or complete complementarity and the aRNA only has a single target RNA. In the latter case, the aRNA comes from a more distant gene. They usually show a lower degree of complementarity, which is why the complexes formed are more unstable and in some cases chaperones are required to stabilize the complex and several RNAs can be the target.

In addition to this classification, classification can also be made either according to the type of interaction (RNA-DNA, RNA-RNA or RNA-protein), the length of the aRNA (the limit is drawn here at 100 bp) or according to the type of promoter concerned. Finally, a classification is sometimes made according to the half-life of the aRNA in the cell, even if the importance of this is subordinate to that of the mating rate between aRNA and mRNA.

Use & occurrence

Antisense-RNA represents a natural possibility of gene regulation of protein biosynthesis . In humans there are at least 1600 antisense genes, for example the insulin-like growth factor 2 receptor (IGF-2). In the case of this gene, depending on its genetic makeup , a second promoter can be active at the 3 'end of the gene , via which antisense RNA is transcribed. This then prevents the translation of both alleles of this gene. The phenotype does not follow the Mendelian genetics . Antisense transcripts occur in more than 70% of the genes in cDNA databases (Fantom-3, GenBank).

Antisense RNA is used, for example, in biotechnology , for example in the commercially less successful Flavr-Savr tomato . Here, an artificial gene was introduced into the tomato that produces antisense RNA against a gene involved in the ripening process that codes for the enzyme polygalacturonase . This can delay the ripening process of the so-called Flavr-Savr tomato. Another example is the Amflora potato , where the technique was used to suppress amylose production in the potato.

In addition to its use in biotechnology, the antisense RNA system is increasingly being used in medicine and pharmacology. The first drug based on antisense technology and approved for sale is the antiviral drug fomivirsen against the cytomegalovirus . C. Frank Bennett (neurodegenerative diseases) and Adrian R. Krainer ( spinal muscular atrophy ) received the Breakthrough Prize in Life Sciences for the development of antisense RNA drugs in 2019 .

In such therapeutic approaches, attempts are usually made to shut down a gene using aRNA. There are two approaches to this. On the one hand, an aRNA for a type of anti-gene can be generated that then binds to the mRNA of the target gene. Alternatively, a 15 to 20 bp long aRNA can be used that targets a specific sequence, which is usually sufficient. One possibility here is to attack the 5 'end of the mRNA and thus completely prevent translation. It is just as easy to bind to any other point within the mRNA, which usually has the same effectiveness.

In molecular and cell biology , in vitro generated antisense RNA is used for in situ hybridizations .

literature

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  7. ↑ Mohammad Ali Faghihi, Farzaneh Modarresi, Ahmad M. Khalil, Douglas E. Wood, Barbara G. Sahagan: Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase . In: Nature Medicine . tape 14 , no. July 7 , 2008, ISSN  1546-170X , p. 723-730 , doi : 10.1038 / nm1784 , PMID 18587408 , PMC 2826895 (free full text).
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  17. ^ RIKEN Genome Exploration Research Group and Genome Science Group (Genome Network Project Core Group) and the FANTOM Consortium: Antisense Transcription in the Mammalian Transcriptome . In: Science . tape 309 , no. 5740 , September 2, 2005, ISSN  0036-8075 , p. 1564–1566 , doi : 10.1126 / science.1112009 .
  18. ^ RA Sanders, W. Hiatt: Tomato transgene structure and silencing. In: Nat. Biotechnol. Vol. 23, 2005, pp. 287-289. PMID 15765076
  19. ↑ BASF: Amflora  ( page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.@1@ 2Template: Dead Link / www.basf.com  
  20. ↑ David P. Clark, Nanette J. Pazdernik: Inherited Defects and Gene Therapy . In: Biotechnology . Elsevier, 2016, ISBN 978-0-12-385015-7 , pp. 523-564 , doi : 10.1016 / b978-0-12-385015-7.00017-x .

See also

Web links