BioWorld International Correspondent
LONDON - The prospect of a new generation of anticancer drugs that can target enzymes exclusive to cancer cells has edged closer, now that scientists have worked out the 3-dimensional structure of telomeres - the "caps" on the ends of the chromosomes.
Stephen Neidle, professor of biophysics at the Institute of Cancer Research in London, whose team made the discovery, told BioWorld International, "It is one of the hallmarks of cancer cells that the lengths of their telomeres are maintained as a result of reactivation of the enzyme telomerase. We plan to use this information about the structure of the telomeres to help us identify drugs that can block their interaction with telomerase."
Neidle, together with colleagues Gary Parkinson and Michael Lee at the institute's Cancer Research UK Biomolecular Structure Unit, reports his work, which was funded by the charity Cancer Research UK, in a letter to Nature of May 26, 2002, titled "Crystal structure of parallel quadruplexes from human telomeric DNA."
Telomeres are repetitive arrangements of proteins and nucleic acids that occur on the ends of chromosomes in all species that have linear chromosomes. They encode no proteins, but protect the chromosome ends from fusing together and from degradation by cellular enzymes.
In normal human cells, they are several thousand bases long. With each round of cell replication, they become progressively shorter until, eventually, they are too short to allow the DNA to be replicated, and the cell dies.
In the majority of tumor cells, however, an enzyme called telomerase is active, allowing the cells to replenish their telomeres and continue to divide. Much research has been directed at trying to exploit this difference between cancer cells and normal cells, whether by turning off the gene encoding telomerase, or interfering directly with the enzyme's action.
Neidle and his colleagues decided to investigate the crystalline 3-dimensional structure of the telomeres in the hope of following the latter strategy. "We knew that the nature of the sequence of bases in the telomeres was such that the DNA could fold up into four-stranded structures - termed guanine quadruplexes - rather than the normal two strands of conventional DNA," he said. "This happens because the structure turns back on itself. But most researchers had expected the crystalline structure of the quadruplexes from human telomeres to be compact and globular."
Instead, to his team's surprise, the structure was disc-like. This finding was, the researchers write in Nature, "remarkable and completely unexpected." The four-stranded structures are flat and can form long stacks one on top of the other, with structures that resemble the blades of propellers sticking out on all sides.
Neidle said, "We found that all the strands of DNA in these quadruplexes are in a parallel orientation to each other. This produces very characteristic looped-out entities which are just sitting there waiting to interact with other cellular proteins."
This has, he added, "profound implications" for how researchers will design small molecules that can interact with these entities. He and his team are embarking on a research program to design such molecules.
Although researchers had previously studied quadruplexes from human telomeres in the presence of sodium ions, the paper by Neidle and his colleagues is the first report of the structure of human telomeres in three dimensions within a physiological environment resembling that found within cells, and in the presence of potassium ions.