Antisense Nucleotides

Messenger RNA (mRNA) is a single-stranded molecule used for protein production at the ribosome. Because its sequence is used for translation, mRNA is called a "sense" strand or sense sequence. A complementary sequence to that mRNA is an "antisense" sequence. For instance, if the mRNA sequence was AUGAAACCCGUG, the antisense strand would be UACUUUGGGCAC. Complementary sequences will pair up in RNA just as they do in DNA. When this happens to an mRNA, however, it can no longer be translated at the ribosome, no protein synthesis occurs, and the "duplex" RNA is degraded.

This phenomenon has been used experimentally and commercially to block the synthesis of specific proteins in transgenic organisms (ones to which a foreign gene has been added). The strategy is to add a synthetic gene that, when transcribed, will make the antisense RNA sequence for the target protein's mRNA.

This technique was first used commercially in 1988 for the FlavrSavr tomato. The gene chosen for inactivation was polygalacturonase (PG), whose enzyme unlinks pectins in the plant cell wall, thereby softening it. The intent was to increase the time the fruit could be left to ripen without softening, thus increasing flavor of commercial tomatoes. The Calgene company created a transgenic tomato plant expressing the antisense RNA for PG mRNA, and reduced PG production by up to 90 percent. Although the tomato was not a commercial success, it demonstrated the potential for this strategy.

Antisense RNA is currently being investigated as a human therapy for certain forms of cancer. The goal is to use gene therapy techniques to insert an antisense gene into tumor cells. Many cancers are due to overexpression of the genes that promote cell proliferation, called tumor suppressor genes. Antisense RNA might be able to inhibit this overexpression. Another target is the BCL-2 gene, whose protein prevents apoptosis, or programmed cell death. In certain cancers, the BCL-2 gene is overactive, preventing death of cells and leading to their proliferation. Antisense therapy against BCL-2 is currently being tested under the trade name Genazyme.

Antisense nucleotides bind to "sense" mRNA, preventing translation of the RNA message at the ribosome, thus preventing protein synthesis. Adapted from <http://www.cem.msu.edu/~cem181h/projects/97/antisense/dia1.gif>.