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Visualizing the end of the human genome

Scientists have glimpsed the three-dimensional structure of a protein that protects the ends of human chromosomes, a function that is essential for normal cell division and survival. By visualizing the protein as it surrounds the end of a chromosome, the scientists have learned how the protein homes in on a specific DNA sequence and acts like a protective cap to prevent erosion of chromosome ends.

The researchers, led by Howard Hughes Medical Institute President Thomas R. Cech, whose laboratory is at the University of Colorado at Boulder, published their findings in an advance online publication in Nature Structural and Molecular Biology on November 21, 2004. Ming Lei and Elaine R. Podell in Cech's lab were co-authors. According to Cech, the findings raise new questions about essential cellular functions taking place at the end of the chromosome.

During normal DNA replication, the very ends of a DNA molecule are lost. In order to prevent erosion, chromosomes are capped with a specialized region of DNA known as a telomere a short, repetitious DNA sequence that does not code for any protein. In humans, an entire telomere is thousands of base pairs long, and is made up of a repeating sequence of six nucleotides. The final 100 to 300 nucleotides at the very end extend beyond the double helix as a single-stranded DNA "tail." The telomeres of normal cells gradually become shorter and shorter with each cell division, a characteristic sign of cellular aging.

But cells also possess a unique enzyme known as telomerase that can lengthen telomeres by adding DNA to the ends of the chromosome using its own RNA template. In most cells, telomerase activity is very low after embryonic development, and regulation of telomerase is critical, because too much telomerase activity can promote tumor development.

In 2001, Dr. Peter Baumann in Cech's laboratory discovered POT1 (for "protection of telomeres"), the only protein known to bind
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
23-Nov-2004


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