Scientists have created the first detailed picture of the molecular structure of the human telomerase enzyme, an advance that may lead to the development of new drugs for ageing and cancer.
Scientists have created the first detailed picture of the molecular structure of the human telomerase enzyme, an advance that may lead to the development of new drugs for ageing and cancer. In the journal Nature, the researchers describe the three-dimensional (3D) molecular structure of human telomerase. “It has been a long time coming. It took a lot of persistence,” said Kathleen Collins, a professor at the University of California, Berkeley in the US.
One bottleneck has been obtaining pure samples of this complex molecule, which is composed of an RNA backbone decorated by six types of protein that move around as they add DNA to the ends of chromosomes, researchers said. Labs around the world have debated whether the enzyme operates singly or as conjoined twins, and how and how many proteins decorate the RNA backbone, they said.
Without consensus on these questions, it has proven difficult to design a drug to target the molecular machine and either destroy telomerase activity – which could stop a cancer that has boosted its telomerase levels – or restart telomerase, perhaps to prime the body for rapid cell division after a bone marrow transplant.
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 for drugs, said Thi Hoang Duong Nguyen, a postdoctoral fellow at UC Berkeley. “The best previous images of human telomerase had a resolution of only 30 Angstroms; we were able to get about 7 to 8 Angstroms resolution using cryoelectron microscopy,” Nguyen said.
“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,” said Nguyen. Telomeres were first detected at a molecular level in the late 1970s by Elizabeth Blackburn, then at UC Berkeley and now at the Salk Institute for Biological Studies in California.
Working with the ciliated protozoan Tetrahymena, she and colleagues showed that the ends of the chromosomes are capped by repeating sequences of DNA. Armed with knowledge of telomere sequence, researchers then showed that telomeres in tissues of multicellular organisms grow shorter each time a cell divides.
The telomeres protect the 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.