Telomere research reveals intriguing paradox

Contact: David Lyons, (505) 665 9198 (00-057)

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LOS ALAMOS, N.M., April 20, 2000 -- They shouldn't be there, deep inside our genetic material. Yet, they are, and as it turns out, it's a good thing.

Researchers from the Department of Energy's Los Alamos and E.O. Lawrence Berkeley national laboratories and the Memorial Sloan-Kettering Cancer Center in New York have made surprising new discoveries about DNA repair proteins and the ends of chromosomes known as telomeres that one day may lead to new paths in cancer research and a better understanding of human cell biology.

The researchers found that, for reasons still unknown, specific DNA repair proteins typically found around broken DNA ends also surround mammalian telomeres, which are natural chromosome ends. Moreover, these same repair proteins are required to maintain normal mammalian telomere functions.

The presence of the repair protein called DNA-dependent protein kinase, or DNA-PK, somehow plays a key role in preventing chromosomes from "fusing" together end-to-end. Chromosomal fusions cause cellular instability, that is, problems when the cell tries to divide, and can lead to cancer in humans.

"DNA repair proteins join broken ends back together, something that normal telomeres want to avoid at all costs," said team member Susan Bailey of Los Alamos' Bioscience Division.

The involvement of DNA repair proteins in telomere maintenance was discovered by other research groups in earlier studies involving yeast chromosomes.

"Beforehand, we had never thought about looking for involvement of DNA repair proteins in normal mammalian telomere function. This study truly is the first of its kind," Bailey said.

Telomeres are known to have important roles in the development of cancers and in the aging process. They are nucleic acid/protein structures that act as "caps" to prevent the DNA in these chromosomal regions from degrading and from being inappropriately joined together.

Los Alamos, a leader in genetic research for decades, provided the first detailed information on the sequence and importance of human telomeres and on the importance of regions of chromosomes called centromeres in cell division.

"When two chromosomes join at the ends, they fuse together and essentially create one long chromosome with two centromeres," explained Bailey. "When cell division occurs shortly afterward, the new cell typically is unstable, either because it has too much genetic material -- and too many centromeres -- or not enough."

If the unstable cell dies, then nothing else happens. If it remains alive, however, the potential for the development of tumors or various cancers increases significantly, she added.

In research published in the December issue of The Proceedings of the National Academy of Sciences, the team reported two significant findings. First, in controlled laboratory tests using a telomeric detection technique called fluorescence in situ hybridization, or FISH, the researchers discovered that the telomeres still were present after fusion occurred between mouse chromosomes lacking DNA-PK.

"Until then, researchers thought that normally fusion could occur only in the absence of telomeres -- that they already had broken off from the chromosomes," said Bailey. Telomeres can break off as a result of radiation exposure, oxidative damage or various other means.

Second, and most importantly, the researchers discovered by comparing many mouse chromosome samples containing normal levels of DNA-PK that telomeric fusion occurred only in the protein-deficient samples. This clearly demonstrated that these proteins are necessary to prevent telomeric fusion in mammalian cells.

The researchers' findings, however, present them with what they call an intriguing paradox.

"Logically, there is no reason for DNA repair proteins to be present around telomeres, since they are not broken ends, and much less reason to suspect that they would actually be required to maintain normal telomeric protection functions," Bailey said. "Through some unknown mechanism, the repair proteins allow a cell to recognize telomeres as natural ends and not broken DNA strands in need of repair."

Additional studies are under way at Los Alamos and elsewhere to try to solve these mysteries.

"Understanding the mechanism involved could lead us into completely new directions in cancer research, perhaps even in gene therapy," said Bailey.

The Los Alamos part of the research team consisted of Bailey, Julianne Meyne, Bruce Lehnert and Edwin Goodwin, all of the Bioscience Division. Other participants were David Chen and Akihiro Kurimasa of Lawrence Berkeley National Laboratory and Gloria Li of Memorial Sloan-Kettering Cancer Center.

Funding for the research was provided by grants from the Department of Energy, U.S. Army and National Institutes of Health.

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