Arthur J. Villasanta – Fourth Estate Contributor
Berkeley, CA, United States (4E) – The first detailed image of the molecular structure of human telomerase, the enzyme that lengthens chromosomes and extends the lifespan of a cell, was published recently by researchers at the University of California, Berkeley.
Telomerase adds short regions of DNA called telomeres to the ends of chromosomes, which prevent the loss of genetic material during cellular replication. It’s inactive in most adult cells, meaning telomeres shorten during our lifetime. Researchers surmise that the shortening of telomeres, which is a complex enzyme, might be responsible for aging. Reactivation of telomerase can be seen in cancer, allowing cells to proliferate uncontrollably.
The discovery of telomerase at UC Berkeley more than 30 years ago triggered enormous interest in the role the enzyme plays in aging and cancer, and sparked efforts to manufacture drugs that can activate or block it.
Although neither anti-aging nor anti-cancer drugs have yet emerged, the image of the enzyme that has now been produced should kick-start the process and enable more targeted drug screening and improved drug design.
One hurdle facing researchers has been the difficulty in obtaining pure samples of telomerase, which has an RNA backbone with six types of protein that add DNA to chromosome ends. Researchers worldwide have disagreed over whether the enzyme operates singly or as conjoined proteins, as well as how many proteins add the DNA.
Without definitive answers to these questions, it’s been difficult to design drugs that can target the enzyme to either destroy it and stop cancer or restart the enzyme, which may trigger rapid cell division.
“It has been a long time coming. It took a lot of persistence,” said Kathleen Collins, a UC Berkeley professor of molecular and cell biology, who has worked on the enzyme for 26 years.
Collins has been trying to determine the structure ever since the first human telomerase protein was discovered in 1997 and is looking forward to discovering more about the assembly of one of the most complex enzymes in the body.
First author Thi Hoang Duong Nguyen said the newly revealed structure still lacks fine detail, but combined with knowledge of the gene sequence of human telomerase, it provides enough information to start thinking about potential targets. Nguyen is also a Miller Institute postdoctoral fellow at UC Berkeley.
“The best previous images of human telomerase had a resolution of only 30 Ångstroms; we were able to get about 7 to 8 Ångstroms resolution using cryoelectron microscopy,” said Nguyen. “When I got to the point where I could see all the subunits — we had 11 protein subunits in total — it was a moment of, ‘Wow, wow, this is how they all fit together.’”
Telomeres were first detected at a molecular level in the late 1970s by Elizabeth Blackburn, then at UC Berkeley and now president emerita of the Salk Institute for Biological Studies in La Jolla, California. Working with the ciliated protozoan Tetrahymena, she and colleagues showed that the ends of the chromosomes are capped by repeating sequences of DNA.
Telomeres protect DNA strands from fraying and getting damaged at their ends, much like the plastic tip on the end of a shoelace. The fact that they drop off with each cell division is thought to protect us from cancer, when a cell is hijacked and proliferates continually.
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