Reference Work Entry

Encyclopedia of Genetics, Genomics, Proteomics and Informatics

pp 121-122


Antisense RNA

Is a transcript of a gene or transposon that may inhibit translation by pairing with the 5′ end of the correct (sense) mRNA and thus prevent its ribosome binding and expression. In several bacterial plasmids, by inhibiting the synthesis of the replication initiator protein, the antisense RNA limits copy number. Some synthetic oligonucleotide analogs may block replication and transcription, interfere with splicing of exons, disrupt RNA structure, destabilize mRNA by interfering with 5′ capping of mRNA, inhibit polyadenylation, activate ribonuclease H. When coupled to alkylating agents they can cross-link nucleic acids at the recognized sequences, can be used as vehicles for targeted DNA cleavage, may inhibit receptors, etc. The various functions require a large variety of specific antisense constructs. Usually, the antisense oligonucleotides are 12–50-nucleotide long. According to calculations in the human genome, any 17-base sequence occurs only once, and in the mRNA populations, 13mer residues are unique. Shorter sequences do not have sufficient specificity. Long antisense sequences may have self-binding tracts that may cause lowered affinity for their target. Natural antisense RNA transcripts (NATs) occur in all types of biological systems, from viruses to higher eukaryotes. This fact indicates that in eukaryotes both strands of the DNA may be transcribed. In the human genome, 2,667 loci were reported as showing transcripts of the complementary strands (Yelin R et al 2003 Nature Biotechnol 21:379). In Arabidopsis ∼30% of the annotated genes displayed significant antisense RNA expression (Yamada K et al 2003 Science 302:842). The cis-NATs are transcribed at the same locus but from the opposite strand of the DNA. The trans-NATs are transcribed at sites different from that where encoding of the sense transcript takes place. The trans-NATs can regulate the expression of several genes like the microRNAs (Wang, X.-J. et al. 2005 Genome Biol 6:R30). Among five species of fungi, the number of genes involved with antisense transcripts is variable (Steigele S, Nieselt K 2005 Nucleic Acids Res 33:5034)

Antisense RNA (or DNA) was expected to become an important therapeutic tool for fighting infections and cancer. This technology is still under development for finding cures against cytomegaloviruses, HIV1, Papilloma virus, autoimmune diseases (arthritis, etc.), leukemia (CMV) and blocking the immune system in case of organ transplants. Surprisingly, the antisense RNA may trigger an immune reaction because the CpG blocks are unmethylated and the animal immune system responds to them as to bacterial molecules. In bacteria these bases are largely unmethylated in contrast to eukaryotes where a substantial fraction of the DNA is methylated. The phosphorothioate oligodeoxynucleotides or oligoribonucleotides are taken up by a variety of cell types, including some prokaryotes (Vibrio), and bind either to DNA, RNA or protein. Phosphorothioate LD50 is about 750 mg/kg. Antisense RNAs may block embryonic development and can be used to inhibit gene expression at defined stages. Although antisense RNA is supposed to be very specifically for the intended target, it may affect several genes that have short or long sequences homologous to the target. A deletion in the hemoglobin gene cluster juxtaposes another gene (LUC7L, an U1Snrp component) to the HBA2 gene, which normally is situated 335–337 bp downstream from the polyA addition site of HBA2 and transcribed in the opposite direction of the hemoglobin gene. The LUC7L is also truncated by the deletion and thus lacks the termination signals and consequently its transcript fuses with the CpG island of HBA2. This condition generates an antisense RNA, which causes complete methylation of the island and silencing of the intact HBA2 and thereby α-thalassemia (Tufarelli C et al 2003 Nature Genet 34:157). In addition, the antisense RNA may bind and affect different proteins as an aptamer. Furthermore, the nucleic acid degradation products concomitant or following the administration of the antisense RNA may also result in unspecific inhibition in the cells. host-pathogen relations, triplex, aptamer, pseudoknot, peptide nucleic acid, phosphorothioate​s, methylphosphonat​es, cap, fruit ripening, anthocyanin, co-suppression, RIP, Cytomegalovirus, Papilloma virus, autoimmune disease, leukemia, transplantation antigens, antisense technologies, sense strand, AS ODN, anticoding strand, coding strand, triple strand formation, RNA double-stranded, hybrid arrested translation, RNAi, G quartet, U1 RNA, thalassemia, Xist, microrna, TUF; Helene C, Toulme JJ 1990 Biochim Biophys Acta 1049:99; Matveeva OV et al 2000 Nucleic Acids Res 28:2862; Sohail M et al 2001 Nucleic Acids Res 29:2041; http://​www.​prl.​msu.​edu/PLANTncRNAs/database.html, natural antisense RNA: http://​natsdb.​cbi.​pku.​edu.​cn/.

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