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September 22, 2023

Structure of telomerase can help advance cancer research

By Mo-Yu Zhou | April 25, 2013

Sometimes, the key to understanding is to take a good, hard look. Scientists have been doing just that, training their eyes on the telomerase enzyme which is known to play a significant role in aging, cancer and other diseases. For the first time, researchers have mapped out the structure of the entire enzyme complex. The researchers from UCLA and UC Berkeley say this breakthrough could lead to new ways of combatting disease, particularly cancer.

The study, published in the April 11 print edition of Nature and led by Jiansen Jiang and Edward Miracco, both of UCLA, managed to make a discovery that many in the field had been itching to achieve, namely, find out what the telomerase enzyme looks like. The findings reported not only the relative positions of the enzyme’s components, but also the organization of the enzyme’s active site. Furthermore, the researchers were able to point out what each component contributed to the enzyme’s biochemical function.

The researchers acknowledge that five years ago, these results would not have been possible. In order to put the puzzle of telomerase’s three-dimensional structure together, Jiang, Miracco, and their co-authors needed to take advantage of cutting-edge technology and a range of different methods. Fortunately, UCLA is home to a highly advanced electron microscopy facility that aided their research.

Telomerase was first identified in Tetrahymena thermophile, a single-celled eukaryotic organism that the researchers of the current study also used to solve the structure of telomerase. This discovery led to the 2009 Nobel Prize in medicine. In particular, research done in the lab of co-senior author Kathleen Collins of UC Berkeley laid the groundwork for this endeavor.

Inside our cells, the protective ends of our chromosomes are known as telomeres. The telomerase enzyme helps maintain these telomeres. Like aglets, the plastic tips at the ends of shoelaces, telomeres protect important genetic information. However, every time a cell divides, these protective telomeres get shorter. At a certain point, the telomeres wear away until they are too short to protect the chromosomes. Just as the shoelaces would start to fray, the erosion of the telomeres causes cell death as part of the normal aging process.

In 80 to 90 percent of cancer cells, telomerase activity is quite high. As a result, telomeres do not shorten as they would with normal cells, extending the life of the cancer cells. This is a significant contributing factor to the progression of cancer.

Most cells, unlike cancer cells, actually have low levels of telomerase. Thus, inhibiting telomerase might slow down the progression of various cancers while not negatively affecting most healthy cells.

Until recently, the development of cancer-fighting drugs that targeted telomerase was hampered by the fact that the structure of telomerase was largely unknown. Now, however, the development of telomerase-targeting pharmaceuticals can finally take into account how the drug might interact with telomerase given the complete visual map provided by the researchers. The model can also be used to screen candidates for cancer therapy drugs.

The research also exposed previously unknown challenges. One surprise was the role of p50, a protein that acts as a sort of hinge in Tetrahymena telomerase. The protein was found to allow for dynamic movement within the enzyme complex, playing a crucial role not only in the activity within the enzyme, but also in recruiting other proteins to join the enzyme complex.

Most importantly, the development of a visual three-dimensional map of the telomerase enzyme seems to have significant implications for the development of drugs to combat a variety of diseases. In particular, the results of this study may provide scientists with a tool to better develop and test drugs that might slow down the progression of cancer cells.

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