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Sci. Aging Knowl. Environ., 23 January 2002
Vol. 2002, Issue 3, p. nw8
[DOI: 10.1126/sageke.2002.3.nw8]


Break Dancing: Werner syndrome protein might keep rowdy enzymes from doing a number on tattered DNA ends (DNA repair)

Caroline Seydel;2002/3/nw8

Key Words: Werner syndrome • WRN • exonuclease • helicase • RecQ • non-homologous end joining

Abstract: As DNA ages, it frays, but the body's ability to mend that damage keeps our cells healthy. People who suffer from the premature aging disorder Werner syndrome lack a protein that's crucial for this repair process (see "Of Hyperaging and Methuselah Genes"). The protein, called WRN, normally unwinds the two strands of a broken double helix and nibbles down the damaged DNA ends so they can be rejoined smoothly. New results suggest that it competes with more destructive enzymes to limit the extent of DNA loss.

During the normal course of its life, a cell encounters many assaults, some of which cause breaks across both strands of DNA. Healthy cells repair this damage through two pathways: homologous recombination, whereby the cell uses the intact strand as a template from which to repair the marred one, and non-homologous end joining, in which cellular machinery chews up short bits of the broken DNA ends and then pastes them together, as one might trim off the damaged section of an audiotape before splicing the clean cuts. This process removes stretches of DNA that range in length from a few base pairs to many thousand.

Werner syndrome patients commonly carry extensive DNA deletions, which probably contribute to the early aging symptoms and high cancer incidence characteristic of the disease. Oshima and colleagues inserted short pieces of DNA with ragged ends into cells with and without functional WRN. Then the team assessed how well the cells patched the ends together; because the terminal sequences weren't similar to each other, they had to be repaired by non-homologous end joining as opposed to homologous recombination. The researchers observed deletions in test molecules that underwent repair in either type of cell--with or without WRN--but DNA molecules from cells that lacked WRN contained extensive deletions more frequently than did those from cells that carried intact WRN. Because WRN itself unwinds the two DNA strands and chews them in preparation for gluing the ends together, the researchers suggest that when WRN binds DNA, it blocks more aggressive enzymes from binding and munching the broken ends.

Previous studies have shown that WRN interacts with cellular proteins known to attach broken DNA ends. Building on those findings, the new work directly assesses WRN's role in the process rather than implicating it by association with other proteins. Subsequent studies are needed to nail down how these cellular interactions contribute to the symptoms of Werner syndrome. It remains to be seen whether the results--obtained in cell culture using small pieces of DNA that don't normally reside in human cells--reflect what happens to chromosomal DNA inside the body. If so, the secret of this protein's powerful influence on the body might lie in its gentle moves.

--Caroline Seydel; suggested by Galynn Zitnick

J. Oshima, S. Huang, C. Pae, J. Campisi, R. H. Schiestl, Lack of WRN results in extensive deletion at non-homologous joining ends. Cancer Res. 62, 547-551 (2002). [Abstract] [Full Text]

Citation: C. Seydel, Break Dancing: Werner syndrome protein might keep rowdy enzymes from doing a number on tattered DNA ends (DNA repair). Science's SAGE KE (23 January 2002),;2002/3/nw8

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