During the process of transcription, double-stranded DNA is separated into two strands by polymerases. These strands are named the sense (coding or [+] strand) and the antisense (template or [—] strand). The antisense DNA strand serves as the template for mRNA synthesis in the cell. Hence, the code for ribosomal protein synthesis is normally transmitted through the antisense strand. Sometimes, the sense DNA strand will code for a molecule of RNA. In this case, the resulting RNA molecule is called antisense RNA. Antisense RNA sequences were first reported to be naturally occurring molecules in which endogenous strands formed comple-mentarily to cellular mRNA, resulting in the repression of gene expression. Hence, they may be natural control molecules. Rationally designed antisense oligonucleotide interactions occur when the base pairs of a synthetic, specifically designed antisense molecule align precisely with a series of bases in a target mRNA molecule.
Antisense oligonucleotides may inhibit gene expression transiently by masking the ribosome-binding site on mRNA, blocking translation and thus preventing protein synthesis, or permanently by cross-linkage between the oligonu-cleotide and the mRNA. Most importantly, ribonuclease H (RNase H) can recognize the DNA-RNA duplex (antisense DNA binding to mRNA), or an RNA-RNA duplex (antisense RNA interacting with mRNA), disrupting the base pairing interactions and digesting the RNA portion of the double helix. Inhibition of gene expression occurs because the digested mRNA is no longer competent for translation and resulting protein synthesis.
Antisense technology is beginning to be used to develop drugs that might be able to control disease by blocking the genetic code, interfering with damaged or malfunctioning genes. Among the possible therapeutic antisense agents under investigation are agents for chronic myelogenous leukemia, HIV infection and AIDS, cytomegalovirus retinitis in AIDS patients, and some inflammatory diseases.
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