Protective Protein Caps Discovered At Ends Of Human Chromosomes

The very end of chromosomes, known as telomeres, contain repeating chains of DNA that protect chromosomes from damage, said Peter Baumann, a Howard Hughes Medical Institute researcher working at the University of Colorado at Boulder. Portions of the telomeres are lost each time a cell divides, a process that may act as a biological clock by signaling the cell to stop dividing after a certain point.

"Scientists have long known about the DNA component of telomeres, and have described the proteins that bind close to the telomere’s end," said HHMI President Thomas Cech, also a distinguished chemistry and biochemistry professor at CU-Boulder and CU’s Health Sciences Center in Denver. "But a protein cap at the very end of the chromosome had been found only in certain single-cell organisms like protozoans and yeast."

A researcher in Cech’s Boulder lab, Baumann spearheaded the discovery that both fission yeast and humans share the newly discovered protein, which has the attributes expected of a telomere end-binding protein. Baumann and Cech dubbed the protein "Protection of Telomeres," or POT-1.

"Part of the beauty of this surprising finding is that this POT-1 protein has been conserved through evolution from single-celled organisms to mammals," said Baumann.

A paper on the subject by Baumann and Cech appears in the May 11 issue of Science.

Cech, who shared the 1989 Nobel Prize in chemistry, became an HHMI Investigator in 1988 while a distinguished professor at CU. He remained a full-time CU faculty member until January 2000, when he became president of the Chevy Chase, Md., -based institute, the nation’s leading privately funded biomedical research organization and one of the world’s leading philanthropies.

Cech retains his CU faculty position, holding weekly teleconferences with his Boulder research team and making monthly visits to Boulder to oversee his lab.

The advantage to finding the protein in fission yeast is that it is relatively simple to "knock out" a gene in the organism in order to understand the importance of the protein it produces, said Baumann. When the POT-1 gene was knocked out, the yeast could not maintain its normal linear chromosomes, and the ends rapidly degraded.

"There has been a great deal of press lately about the human genome, the DNA sequence that encodes all that it takes to define the human species and also to give each of us our individual characteristics," said Cech. "But also important are the proteins that keep the DNA organized and protected and allow certain genes to be expressed at the right time."

With several genomes including humans now sequenced, Baumann and Cech were able to use computer data to look for POT-1 genes in other sequenced organisms. They eventually found "a good match" to the fission yeast POT-1 gene in the human genome.

When the yeast and human POT-1 proteins were made in the lab, they were found to have the expected DNA end-binding property in test tubes, Cech said. The fission yeast POT-1 protein bound to yeast telomeric DNA, while the human POT-1 protein bound to human telomeric DNA.

Both Cech and Baumann stressed that the discovery is so new that the medical implications likely will take some time to emerge. Since the replication of telomeres is a process that is activated in most human cancers, the POT-1 protein may play a role in regulating telomere replication, said Cech. "If so, drugs that altered its ability to bind DNA might provide new chemotherapeutic agents," he said.

In addition, telomere replication in the laboratory can allow for continuous proliferation, or "immortality" of human cells, so the POT-1 protein could have implications for the aging process. "Only time will tell," said Baumann.