Volume 6, Issue 46 September 2009
The Immortality Enzyme
Kathleen Collins is also a principal investigator with the Berkeley Stem Cell Center. Image credit: Leath Tonkin
Most people need a clock to keep track of time. Cells, however, need no such crutch; their timepieces are built right into their chromosomes. These segments of DNA, which cap chromosomes, get trimmed with each subsequent cell division. Called telomeres, they can only get so short before a cell stops dividing and dies.
Some cells, however, employ a remarkable enzyme known as telomerase to lengthen both telomeres and their lifespans. These powers make telomerase a suspect of great interest to those studying cancer and the ravages of aging.
Kathleen Collins, a Berkeley professor of cell and molecular biology, has made it her business to understand everything she can about this so-called immortality enzyme. Her discoveries about its regulation, assembly and connections to human disease are leading the way toward methods to regulate its production and perhaps treat disorders such as cancer.
Telomeres cap the ends of chromosomes. Image credit: NASA
By studying telomerase in the aquatic protozoan Tetrahymena thermophila, Collins was able to identify a number of the important proteins associated with telomerase and its production. These single-celled organisms produce a constant supply of telomerase in order to reproduce. By contrast, only a few human tissues, such as bone marrow and skin cells, make any telomerase at all.
In 1999, the Collins laboratory linked one of these proteins, called dyskerin, to a rare genetic disease. Patients with dyskeratosis congenita, or DKC, seem normal at birth but eventually develop serious skin lesions, lung scarring, and bone marrow failure. "It turned out they had mutations in dyskerin that crippled telomerase," Collins says. With abnormally lower levels of telomerase, the skin, lung, and blood cells, which rely on an occasional telomere boost to constantly renew themselves, essentially ran out of cell divisions. "That offset from telomerase isn't enough to make those cells live forever. But it's enough to get them through the lifespan of long-lived organisms such as humans," she says.
As most human cells divide, their telomeres shorten, eventually arresting cell proliferation. Some cells transformed with viruses or oncogenes can ignore this checkpoint, allowing continued cell division and chromosome rearrangements that cause cell death (crisis). Rarely, cells can activate telomerase to maintain their telomeres, allowing them to turn cancerous. Image credit: Kathleen Collins
Since this discovery, scientists have identified a growing list of disorders that appear linked to diminished telomerase activity. That comes as no surprise to Collins. Her research indicates that the hybrid structure of telomerase, and the elaborate recipe required to create it, makes its assembly fraught with potential complications.
Telomerase is different from most human enzymes in being a kind of biological alloy. It is formed not only from protein but also RNA, the chemical language many viruses use to store genetic information. "It's not just two premade parts that are stuck together," Collins says. "It's a mixed substance that is more than the sum of its parts."
Making telomerase, Collins has found, involves shuttling component parts to different assembly depots within the cell, where a different set of protein workers completes another step in the long list of telomerase building instructions. Hiccups in this assembly line can lower production as well as cause defects in the completed enzyme. These likely account for the wide spectrum of problems seen in DKC and other patients with telomerase defects.
Image credit: Ciliate Genome Sequence Reveals Unique Features of a Model Eukaryote. Robinson R, PLoS Biology Vol. 4/9/2006, e304.
"We don't know how many cellular machines are involved in the assembly of telomerase. Every time we think we've got them all, we discover another layer of complexity," Collins says.
As a functional blend of RNA and protein, Collins says, telomerase is leading an evolutionary trend. Life forms grew more complex largely by developing a larger and more diverse palette of proteins. "We think that in the presence of this great diversity of proteins, evolution more recently has been progressing in part by elaborating protein associations with RNAs. By cofolding one RNA molecule and one protein in different ways, you can get totally new functions," she says. This may help explain why the genomes of humans have only a third more protein-coding content than those of simple roundworms. Collins terms this trend the Ribonucleoprotein or RNP Renaissance.
"There is an appreciation now of that enormous complexity of RNA that we've missed. We have to understand how this integrates into the world we were looking at before," Collins says.