Study provides previously unseen structure of telomere-controlling enzyme.
An enzyme called telomerase plays a significant role in aging and most cancers. Telomerase’s primary job is to maintain the DNA in telomeres, the structures at the ends of a person’s chromosomes that act like the plastic tips at the ends of shoelaces. When telomerase isn’t active, each time cells divide, the telomeres get shorter. When that happens, the telomeres eventually become so short that the cells stop dividing or die. However, until recently many aspects of the enzyme’s structure could not be clearly seen to counteract these many findings.
Now, researchers from UCLA and UC Berkeley have produced images of telomerase in much higher resolution than ever before, giving them major new insights about the enzyme. The team state that their findings could ultimately lead to new directions for treating cancer and preventing premature aging. The study is published in the journal Science.
Previous studies show that telomerase is particularly active in cancer cells, which helps make them immortal and enables cancer to grow and spread. Researchers believe that controlling the length of telomeres in cancer cells could be a way to prevent them from multiplying. On the other hand, cells with abnormally active telomerase can constantly rebuild their protective chromosomal caps and become immortal. Making cells immortal might sound like a promising prospect, however, it actually is harmful because DNA errors accumulate over time, which damages cells.
Earlier studies from UC San Francisco professor Elizabeth Blackburn revealed that telomerase was responsible for maintaining the ends of the chromosomes, however, the study didn’t connect telomerase to cancer and it provided little information about its structural biology. The research was conducted using tiny, single-celled microorganisms called Tetrahymena thermophila that are commonly found in freshwater ponds. Blackburn won a Nobel Prize in 2009 for the finding. Since then the group have been filling in pieces of the telomerase puzzle, also using Tetrahymena. The current study found that the microorganism’s telomerase is more analogous to human telomerase than previously thought.
The current study used cryoelectron microscopes, nuclear magnetic resonance spectroscopy, X-ray crystallography, mass spectrometry and biochemical methods to provide an understanding of where the different components of telomerase interact. The team state that researchers had previously thought telomerase contains eight sub-units, seven proteins and an RNA. However, results show two additional proteins, Teb2 and Teb3, that increase telomerase’s activity. The lab were aware that the RNA strand interacts with the proteins, however, not exactly where it interacted. The new study found that within the enzyme’s ‘catalytic core,’ which is formed by the RNA and its partner proteins TERT and p65, the RNA forms a ring around the donut-shaped TERT protein.
The group state that research had previously shown that telomerase contains three proteins, p75, p45 and p19, however, their structures and functions were poorly understood. Data findings identified the proteins’ structures and revealed that they are similar to proteins found at human telomeres. The results showed that a key protein called p50 interacts with several components of telomerase, including TERT, Teb1 and p75, and this network of interactions has important implications for telomerase’s function.
The lab explain that they knew that the Tetrahymena enzyme’s catalytic core, where the majority of the telomerase activity occurs, was a close analogue to the catalytic core in the human enzyme, however, it was not previously known whether the other proteins had human counterparts. Results show that nearly all, if not all, of the telomerase proteins in Tetrahymena have similar proteins in humans. The lab state that to their knowledge this is the first time that a whole telomerase directly isolated from its natural workplace has been visualized at a sub-nanometer resolution and all components are identified in the structure. The team conclude that the global medical community can now use this new model system to learn more about how telomerase interacts at the telomeres.
The team surmise that they are working to fill in even more details of the telomerase puzzle, and go on to add that their research could lead to the development of pharmaceuticals that target specific sub-units of telomerase and disrupt interactions between proteins. For the future, the researchers state that there is so much potential for treating disease once the global medical community understands how telomerase works.
Source: UCLA Newsroom