Target for Repairing Damaged Cells Found In the Telomerase Enzyme
(Editorial Note: I think that this area of telomerase research is an exceedingly exciting and pregnant domain in terms of its role in prolongevity. This could be a research venue for a "Manhatten Project" aimed at teasing out what we need to know for youth extension, or possibly, youth renewal. Stay tuned!)
of California San Francisco researchers have discovered a region
in the telomease enzyme that could prove to be a target for regenerating
damaged cells. When activated, telomerase replenishes telomeres by copying
the RNA folded within it into telomeric DNA and assembling it on the ends
of the chromosomes. Telomerase is inactive in normal adult tissues, but
it sactive when massive amounts of cell division are underway, as in self-renewing
cells of the immune system, during the development of an embryo, and in
Telomerase and other so-called reverse transcriptases contain RNA enfolded in protein. As such, they are know as ribonucleoproteins. Most enzymes, by contrast, contain only protein. Some researchers believe that in the evolutionary past, it was the RNA component of telomerase that played the catalytic role as the active part of the transcriptase, but that over time, the RNA might have deferred its enzymatic power to the protein. To date, research on telomerase and HIV has focused only on the protein components, since they make up a central part of the enzymes' active sites. However, in the UCSF study, reported in the May 5 issue of Science, the researchers determined that a small structure within the RNA molecule of yeast telomerase controls the precision with which the enzyme carries out its key function -- spinning out the repeated sequences of telomeric DNA that bind the ends of chromosomes. When they disrupted this small region of RNA, the enzyme began to spin out telomeres uncontrollably, until they stalled out like a car run into a ditch. This result occurred in culture and in the yeast cells themselves. Cell death soon ensued.
Inasmuch as the human version of telomerase appears to have a structural region that is similar to that examined in the yeast enzyme, the region could prove to be a target for killing cancer cells, says the senior author of the study, Elizabeth Blackburn, PhD, UCSF professor of microbiology and immunology and biochemistry and biophysics, who co-discovered telomerase in 1985. (The function of the human version of the region has not been determined.) Moreover, she says, it could prove a target for regenerating cells that have been damaged through injury or wear and tear.
The discovery that the seemingly archaic RNA retains a key mechanistic role in telomerase function builds support for the theory that telomerase -- and reverse transcriptases such as HIV -- represent an intermediate step in the evolution of enzymes from strictly RNA sequences to strictly protein sequences, says Blackburn.
"Such a direct function for the RNA structure in the enzymatic action of telomerase supports an evolutionary scheme in which RNA enzymes acquired protein components evolving into ribonucleoprotein enzymes," she says. "The RNA components then gradually lost their functional roles in catalysis and were subsequently dispensable."
Telomerase and the other reverse transcriptase enzymes function by synthesizing copies of DNA from the RNA folded within their protein. Nearly all organisms have an enzyme that can stimulate the conversion of DNA, which contains an organism's genetic code, or genes, into messenger RNA, the first step on the road to developing protein. Only the reverse transcriptases do the opposite. Telomerase and the other reverse transcriptase enzymes function by synthesizing copies of DNA from the RNA folded within their protein. Nearly all organisms have an enzyme that can stimulate the conversion of DNA, which contains an organism's genetic code, or genes, into messenger RNA, the first step on the road to developing protein. Only the reverse transcriptases do the opposite.
Telomerase draws in only a very small portion of its long RNA sequence to the catalytic site, and copies this one segment, known as the template, over and over into telomeric DNA, which it then assembles and adds to the ends of chromosomes.
Until now, researchers have not understood what specifies the enzyme's template boundaries, preventing unbridled spinning of telomeric DNA onto the ends of chromosomes. In the current study, the researchers determined that the limitation on DNA synthesis is controlled by a small segment of RNA nestled up adjacent to the downstream end of the RNA template. The region, made up of base pairs of RNA that are "zipped up" together within a large segment of RNA, acts as a boundary for the replication process.
When the researchers altered this RNA region, the buffer "unzipped," providing a long strip of RNA - up one side of the zipper -- for the enzyme to continue converting into DNA. With free reign, the enzyme drew more and more of the ribonucleotides into its active site, until it synthesized so much telomeric DNA that eventually, says Blackburn, the telomerase RNA may have bunched up, halting telomere synthesis and causing cell death. Such abnormal, almost ceaseless, replication, says Blackburn, is reminiscent of the behavior of normal reverse transcriptases such as those found in retroviruses like HIV.
Co-authors of the study were Yehuda Tzfati, PhD, postdoctoral researcher, Tracy B. Fulton, graduate student and Jagoree Roy, PhD, postdoctoral researcher, all of the UCSF Department of Microbiology and Immunology.
The study was funded by the National Institutes of Health.