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Alternative Splicing of Telomerase as a Target for Cancer Treatment
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Whenever DNA is replicated, DNA polymerase, the enzyme that links together the nucleic acids, is unable to add nucleotides to the 3’ end of the chromosome. It requires several nucleotides as overlap in order to “hang on” to the DNA molecule. In order to prevent the chromosome from being shortened significantly with every replication, the cell produces an enzyme called telomerase. Telomerase adds a short sequence of nucleotides to the 3’ end of the DNA molecule. This provides a handle for the polymerase so that it can complete replication of the chromosome. Telomerase gets its name from telomeres, the extra stretches of nucleotides at the end of the chromosome that help protect the chromosome from being shortened during replication. Telomeres can be thought of as analogous to the little plastic ends of shoelaces, which help prevent the lace from unraveling after use.

Telomerase is generally very active during early development, in order to allow for the necessary replication of cells to help the organism grow. Eventually, the telomerase becomes less active, or is even turned off completely. This is believed to help prevent the cell from replicating too many times or too frequently. The absence of functional telomerase is associated with aging. As the cells replicate more and more, the chromosomes have a greater chance of being damaged due to shortening of the telomeres. This damage to the DNA can cause many symptoms of aging. Some scientists have proposed that by reactivating telomerase in cells, the aging process can be prevented. This could be particularly important in adult stem cells, which lose their ability to differentiate effectively as telomeres shorten. However, reactivating telomerase may also have many drawbacks. It could permit uncontrolled replication of cells that have developed mutations, leading to cancer.

Telomerase has been shown to be over-expressed in many different types of cancers. This may be due to the fast replication of cancer cells. Because cancer cells replicate indiscriminately, they need telomerase to help prevent the chromosomes from being shortened and damaged with each replication. Researchers have suggested that by stopping the action of telomerase in tumor cells, they could potentially stop the replication of the cancer cells. Indeed, early studies demonstrated that many cancer cells had telomeres that were dramatically shorter than those seen in normal cells. When researchers treated cells with viral proteins to induce constant replication, many of the cells died after the telomeres had been depleted. However, some cells eventually were able to produce telomerase, and survived, albeit with much shorter telomeres than normal. This indicated to the researchers that telomerase was not activated immediately in rapidly replicating cells. Once the telomerase is activated, however, it can prolong survival of the cells. The highly active telomerase in cancer cells can maintain the shortened telomeres enough to allow for rapid proliferation of the cancer.

Recently, researchers discovered that regulation of telomerase appears to be different than regulation of many other genes. This regulation is related to alternative splicing of the gene. In eukaryotes, alternative splicing allows one gene to encode multiple proteins. The parts of the gene that are spliced together to make the mature mRNA are generally determined by codes in the DNA that are near or within the gene. However, researchers noted that the regulatory DNA sequences for splicing the telomerase gene were more distant from the protein coding portion of the gene. This indicates that alternative splicing of telomerase is regulated in a manner different than most other genes.

Many of the alternative splice variants of the telomerase gene produce an inactive protein. However, the researchers also found some splice variants that functioned, albeit at a much lower efficacy than normal telomerase. By targeting the manner in which telomerase splicing is regulated, the researchers propose that they could effectively turn of telomerase genes in cancer cells. This would result in telomeres eventually disappearing in the cancer cells, and the cancer cells being unable to continue replicating at their advanced rate. Eventually, the cancer cells would die off, due to the damage to their chromosomes. The researchers are excited about this new strategy to control expression of telomerase. By decreasing telomerase activity, they propose to treat cancer. By increasing telomerase expression, they could potentially be able to treat conditions associated with aging.


References:

http://www.sciencedaily.com/releases/201...160713.htm

www.scientificamerican.com/article.cfm?id=telomeres-telomerase-and

http://en.wikipedia.org/wiki/Telomerase
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