Scientists have identified the structure of a key part of the enzyme telomerase, which is known to help cancer cells multiply.
Discovering how this enzyme carries out its functions and protects the ends of chromosomes could lead to the discovery of valuable new targets for cancer drugs, the University of California, Santa Cruz reported. Repetitive DNA sequences at the ends of chromosomes, also known as telomeres, act in a similar fashion at protectors at the end of shoelaces. When cells divide, their telomeres get progressively shorter until the cell can no longer proliferate. The telomerase enzyme has the unique ability to lengthen these telomeres by adding to the repetitive DNA sequence, and this also occurs in tumor cells.
"Since the discovery of telomerase and its over-activation in cancers, people have recognized the huge therapeutic potential for anticancer drugs that target telomerase. But there still is no such drug in the clinic, and part of the reason is our lack of understanding of the detailed structure of the enzyme," said Michael Stone, associate professor of chemistry and biochemistry at UC Santa Cruz and senior author of the paper.
Telomerase is made up of a protein component and an RNA component: the protein is a type of enzyme known as reverse transcriptase that can make copies of DNA and RNA. The RNA component provides a template that allows the enzyme to generate new telomere DNA sequences.
"The template is the track that the enzyme train runs along, and what's so unique with telomerase is that the track is an integral component of the enzyme itself," Stone said.
Reverse transcriptase copies the same short segment of RNA template to create repetitive DNA. Scientists have been trying to work out if how this copied sequence is so precisely defined considering it is a relatively small segment of the much larger telomerase RNA. By solving the structure of a region called the binding domain, the researchers were able to explain how the "how the boundary of the template is defined by the interplay between the protein and RNA components of the telomerase."
The findings showed this binding domain tethers one end of the RNA so only one defined sequence can move through the active section of the enzyme where copying occurs. While the enzyme copies the template sequence, it also pulls the RNA through the active site in what has been called a molecular "tug of war" between the binding domain and the reverse transcriptase. This phenomenon halts the movement of RNA into the active site.
"The reverse transcriptase is pulling on the RNA, but the structural resistance of the RNA binding domain prohibits the movement of more RNA, and that's how the template boundary is defined," Stone said.
Once this occurs, the enzyme is reset to the beginning of the template sequence, and the section of RNA that is tethered forms a structure called an RNA stem loop and a protein structure in the binding domain anchors the RNA stem in place.
"Our model is consistent with the findings of other studies of telomerase and directly reveals the functional mechanism involved," Stone said. "What makes this interesting for rational drug design is that template boundary definition is a very specific feature of telomerase. Our cells are full of other kinds of polymerase enzymes, so it's important to design a drug that targets only telomerase."
The findings were published in a recent edition of the journal Nature Structural & Molecular Biology.
