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Visualizing the end of the human genome

to human telomeric DNA tails. Pot1 plays an important role in capping the ends of chromosomes and in regulating telomere length. "Before that discovery," he said, "people weren't even in agreement that there was a protein at the very ends of human chromosomes." At the same time, Cech's team found a version of the POT1 protein in fission yeast. Other versions of POT1 have since been found in plants and mice each recognizing a telomeric sequence that is unique to that organism.

POT1 is critical to normal cell division and survival; experiments in fission yeast have shown that without it, most cells die immediately. Cells that do manage to survive quickly lose their telomeres, which interferes with normal cell division and eventually leads to massive DNA errors and abnormal, circular chromosomes. In human cells grown in the laboratory, too much POT1 can be disruptive, causing abnormal lengthening or shortening of telomeres.

Prior to determining the structure of human POT1, the researchers' prediction of what it might look like was based on their understanding of the yeast version of the protein. In yeast, POT1 wraps around the end of a chromosome via a region known as an oligonucleotide/oligosaccharide-binding fold (OB-fold) a shape found in many proteins that recognize and bind to DNA or RNA. The repeating six-nucleotide telomeric unit fits precisely within this fold, with many POT1 molecules binding to each chromosome end.

Cech and his colleagues expected human POT1 to have a similar design, but the results of their biochemical analyses of the protein did not fit easily with this model. For example, when the scientists added the protein to short pieces of DNA containing the six nucleotides that make up a human telomeric repeat, the human POT1 protein bound poorly.

To their surprise, they found that POT1 required a stretch of telomeric DNA containing at least ten nucleotides for efficient recognition and bindin
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
23-Nov-2004


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