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Chromosome protection scoops Nobel

October 5, 2009 By Alison A Abbott This article courtesy of Nature News.

Prize for physiology or medicine awarded for uncovering role of telomeres.

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Three US scientists have won the Nobel Prize in Physiology or Medicine for discovering the structure of molecular caps called telomeres and working out how they protect chromosomes from degradation. Their discoveries in cell biology during the 1980s and 1990s opened new avenues of work, in ageing and in cancer research, which are still highly active today.

The prize, announced on 5 October, is shared equally between Elizabeth Blackburn at the University of California, San Francisco, Carol Greider of the Johns Hopkins Medical School in Baltimore, Maryland, and Jack Szostak at Harvard Medical School in Boston, Massachusetts. The three have already won numerous prizes for their work, including sharing one of the 2006 Lasker awards, often considered to be a forerunner of the Nobel prize.

Their research revealed a fundamental aspect of how DNA, packed into chromosomes, is copied in its entirety by the DNA polymerase enzyme during cell division. The ends of the chromosomes are capped by telomeres, long thought to have a protective function (see ). Without them, the chromosomes would be shortened during each cell division, because DNA polymerase is unable to copy to the very end of one of the two DNA strands it is replicating.

In the early 1980s, after their fortuitous meeting at a Gordon Research Conference in 1980, Blackburn and Szostak discovered that telo­meres include a specific DNA sequence. Fired up by the novelty of each other's work, they devised experiments that seemed crazy at the time, even to themselves. Szostak took the telomere sequences that Blackburn had identified in the protozoan Tetrahymena thermophila and coupled it with mini-chromosomes that he inserted into his own preferred model organism, yeast.

Cross-species effect

The sequence was able to protect the chromosomes in this different species1. It was soon found that the protection conferred by telomeres is a fundamental biological mechanism present in nearly all animals and plants. Szostak and Blackburn suspected that an unknown enzyme must be involved. On Christmas Day in 1984, Greider — then Blackburn's postdoc — saw the first evidence that this enzyme, which Greider and Blackburn named telomerase, was responsible for constructing telomere DNA2.

They worked out that telomerase provides a platform enabling DNA polymerases to copy the entire length of the chromosome without missing the ends. Greider and Blackburn also showed that telomerase contains a key RNA sequence that acts as a template for the telomere DNA3, which attracts proteins to form a protective cap around the ends of the DNA strands.

Telomeres themselves shorten with repeated cell division, making up a key part of the cell's ageing mechanism. Low telomerase activity and telomere shortening speed up ageing, whereas incessantly dividing cancer cells often have high telomerase activity and maintain their telo­mere length. Cancer therapies directed against telomerase are now being tested in clinical trials.

But there is still a lot of basic biology to discover — such as how telomerase activity is regulated at individual telomeres, and how telomeres manage to avoid the attentions of DNA repair enzymes which seek out breaks in DNA and restitch the torn ends.

Blackburn and Greider become only the ninth and tenth female scientists to win the physiology or medicine prize since it was first awarded in 1901, and it is the first time that two women have been recognized in a single prize. Indeed, telomere research is unusually dominated by women. "It is hard to find a male among us," says David Shore, a cell biologist at the University of Geneva, Switzerland. "And two main reasons are Liz and Carol — they created the field and have been role models."

Blackburn has also been involved in the politics of science, serving on the US President's Council on Bioethics from 2002 until she was dropped in 2004 after criticizing the restrictions on human embryonic stem-cell research imposed by then President George W. Bush.

Lea Harrington, Greider's first graduate student, who is now at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, UK, says that her four years in Greider's laboratory at Cold Spring Harbor, New York, were "electric. We all realized what an exciting time it was — so many questions being answered about the composition of telomerase, how it worked and its relevance to human biology."

References

  1. Szostak, J. W. & Blackburn, E. H. Cell 29, 245-255 (1982).
  2. Greider, C. W. & Blackburn, E. H. Cell 43, 405-413 (1985).
  3. Greider, C. W. & Blackburn, E. H. Nature 337, 331-337 (1989).

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