A study estimates that researchers discovered telomerase, an enzyme that lengthens chromosome ends and prevents them from fraying enough to kill a cell, speculation ran wild about its role in ageing and cancer, setting off a full-court press to produce drugs to activate or block the enzyme. Cryo-electron microscopy images reveal details of protein, RNA binding and possible drug-target sites. The study was published in the journal Nature.
A detailed picture of the molecular structure of human telomerase should jump-start that effort, allowing more targeted drug screens and intelligent design of new drugs. One bottleneck has been obtaining pure samples of this complex molecule, which is composed of an RNA backbone decorated with six types of protein that move around as they add DNA to the ends of chromosomes.
Telomerase tops up the telomeres
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. Scientists have since found that, in humans and other multicellular organisms, telomerase is expressed only in the embryo, not in most adult cells.
That means that most cells at birth have a predetermined ability to grow and divide, after which they die. Many scientists believe that depleted telomeres are a major cause of ageing. Collins has been trying to determine the structure of telomerase ever since the first human telomerase protein was discovered in 1997, and she and her colleagues have discovered and extensively characterized many of the proteins in the large enzyme, as well as the broken-up hairpin structure of the RNA backbone of telomerase.
Nguyen was able to isolate the active enzyme and purify it much better than anyone had before and employed a new, state-of-the-art cryoelectron microscope to determine the structure of the active telomerase unambiguously. Cryo-EM is a technique for determining molecular structures of compounds that cannot be crystallized and imaged with X-rays.
In 1999, Collins discovered the first known human disease caused by a telomerase mutation: a mutation in a telomerase protein called dyskerin that is responsible for a rare disease called dyskeratosis congenita. The reason, Collins says, is that there are two dyskerin molecules bound to the RNA backbone that have to not only reach out to the network of other proteins but also touch one another, and disease-causing mutations prevent these linkages, crippling the ability of the RNA backbone to survive in cells.
Those with half the normal level of telomerase typically reach a health crisis in mid-life. Collins is ecstatic to have a definitive structure for telomerase finally and looks forward to learning more about the intricate assembly process of one of the most complex enzymes in the body: a polymerase as complicated as the ribosome, which reads RNA to produce proteins.