link Poking holes in the telomere patch

(Originally published in ASBMB Today)

Cancer often is defined loosely as cell division gone awry. For several years, researchers have struggled to find ways to tame this awry cell division while minimizing adversity to normal cells. Radiation, chemotherapy and surgery are conventional methods for ridding the body of cancerous cells, albeit not without harming neighboring bystander cells. Thus, contemporary efforts in cancer research focus on identifying traits that make a cancer cell different from a normal cell and developing precise therapeutics targeted at those traits.

One such trait is the presence of telomerase in a majority of cancer cells. Telomerase, a ribonucleoprotein, synthesizes telomeric DNA (telomeres) during replication. Telomeres are unique complexes of protein and DNA that cap the ends of chromosomes and protect them from abnormal fusion events. However, during each round of replication, some telomere is lost because polymerases are unable to replicate the extreme ends of genomic DNA. This eventually leads to enough erosion of the telomere to cause cells to stop dividing and die off. In cancer cells, however, the presence of the telomerase prevents erosion of telomeric DNA, enabling cells to divide continuously.

Based on this principle, the research group led byThomas Cech at the University of Colorado is developing strategies to block telomerase activity to engender cancer cell death. The TPP1 protein of the telomere exhibits a patch of amino acids on its surface called the TEL patch. This patch is responsible for recruitment of telomerase to the telomere. In their recent study published in The Journal of Biological Chemistry, Cech’s team demonstrates that introducing mutations in the TEL patch to disrupt its activity while chemically inhibiting telomerase causes a decrease in proliferation of HeLa cancer cells correlated with a suppression of telomere elongation.

The group concludes that the pathway for cell death observed in their system is apoptosis as determined by detection of cleavage of the executioner caspase-3 and an increase in annexin V-positive cells in TEL patch mutant cell lines.

The study is significant because it demonstrates the requirement of the TEL patch in cancer cell viability. Based on the findings, inhibiting telomerase recruitment could serve as a precise therapeutic target. It will be interesting to look out for follow-up studies designed to identify small molecules that inhibit telomerase activity in various cancer cells and assess their efficacy in clinical trials.

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