Scientists at UC Santa Cruz have discovered a key structure within the enzyme telomerase, which is active in many cancer and facilitates the cells ability to proliferate uncontrollably. These findings reveal the mechanism via which the enzyme protects the ends of chromosomes and potentially functions to develop tumors.
Role Of Telomeras: Insights Into Preventing Cancer
Telomeres are repetitive sequences of DNA found at the ends of chromosomes. With every cell division, these ‘caps’ become progressively shorter, and ultimately the cell stops dividing. The enzyme telomerase functions to replicate and elongate the telomeres during cell division. It is very active in cells that need to divide indefinitely, such as stem cells, and is also functional in 90 percent of cancerous tumors.
According to senior author Michael Stone, Associate Professor of Chemistry and Biochemistry at UC Santa Cruz, the discovery of the over-activation of telomerase in cancer cells has led to the development of various anti-cancer therapies and drugs targeting the enzyme. However, no such drug is in clinical use, due to the lack of understanding of the complete structure of the enzyme.
Preventing Cancer: Insights Into The Structure
Telomerase is a rather unusual enzyme, having both a protein and an RNA component. The protein component functions as an enzyme and is called reverse transcriptase, which converts DNA into RNA sequences. The RNA component provides this protein enzyme with the template needed to produce the telomere DNA sequence.
“The template functions as a track used by the enzyme train to run along. What’s unique about telomerase is that the track is a vital component of the enzyme itself”, explained Stone.
How The Enzyme Functions – Novel Discoveries
Basically, the enzyme repeatedly copies the same segment of the RNA template in order to produce the recurring DNA sequences at the ends of the chromosome. What was mysterious for scientists was how this copied sequence was so precisely defined.
Stone and his colleagues resolved the structure of a region known as the ‘RNA binding domain’, and revealed how the boundary of the template is defined via associations between reverse transcriptase and the RNA components of telomerase.
“The reverse transcriptase pulls on the RNA, but the structural resistance of the RNA binding domain inhibits the movement of any more RNA. This is how the template boundary remains defined”, Stone explained.
Moreover, the researchers also showed that the part of RNA tethered to the protein forms an ‘RNA stem loop’. This, along with a protein structure within the binding domain, is lodged into the base of the RNA stem, keeping the RNA segments anchored and defined.
Preventing Cancer: A New Drug To Prevent Cancer
Stone highlighted that their model corroborated with previous findings relating to telomerase, and provided direct insights into its functional mechanisms.
“What makes these findings interesting for a coherent drug design is the fact that the definition of the template boundary is an extremely specific feature of telomerase. Our cells contain various kinds of polymerase enzymes, hence it’s important to design anticancer drugs that target only these specific telomerase”, concluded Stone. The study was published on October 5 in Nature Structural & Molecular Biology.