Sci. Aging Knowl. Environ., 27 March 2002
Vol. 2002, Issue 12, p. nw40
[DOI: 10.1126/sageke.2002.12.nw40]

NOTEWORTHY ARTICLES

Twisted Logic: Discoveries tangle Werner syndrome helicase story (Werner syndrome)

R. John Davenport

http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/12/nw40

Key Words: helicase • nonhomologous end joining • DNA repair • progeria

Abstract: TAHOE CITY, CALIFORNIA--Two new studies clash about molecular events that regulate a protein responsible for the premature aging disease Werner syndrome. One suggests that the protein collaborates with a known repair system, whereas the other raises the possibility that it might call different repair equipment into action. Unraveling these findings might eventually shed light on how the protein triggers disease.

Patients with Werner syndrome live in fast-forward because deficiency of a protein leaves their genomes unprotected (see "Of Hyperaging and Methuselah Genes"). The protein, called WRN, normally unwinds and chews up DNA, activities required for mending damaged sections and keeping genetic information from getting garbled. Without WRN, patients suffer from chromosomal rearrangements and deletions. Last year, scientists showed that WRN binds to a protein called Ku. When DNA breaks, Ku gloms onto the exposed ends and attracts another protein called DNA-PKcs. By adding phosphates to other proteins, DNA-PKcs goads repair machinery into action. WRN's connection to Ku suggested that it helps fix DNA by working with that system, and previous work hinted that WRN sticks to DNA-PKcs. Now two studies investigate that link.

Parimal Karmakar and colleagues at the National Institute on Aging in Bethesda, Maryland, used antibodies to pull WRN from cultured human cells and found that DNA-PKcs came along, suggesting that the two proteins hang out together. To find out whether the pair hustles to sites of DNA breakage, the researchers studied the behavior of purified molecules in a test tube. They first bound Ku to DNA molecules with broken ends and then added WRN and DNA-PKcs. Both proteins joined Ku on the cracked molecule. The team also found that DNA-PKcs adds a phosphate group to WRN after the two proteins bind to Ku and DNA--in cells as well as in the test tube. Furthermore, the presence of both Ku and DNA-PKcs hindered WRN's ability to nibble DNA and unravel it. The fact that DNA-PKcs regulates WRN activity suggests that they act together in a single repair system.

But a second study suggests that WRN and DNA-PKcs might not hook up. In work presented here at the DNA Helicases, Cancer, and Aging Keystone Symposium, Lucio Comai of the University of Southern California in Los Angeles and colleagues report that WRN boots DNA-PKcs off the DNA ends. Instead of joining Ku and DNA-PKcs on the DNA, WRN took DNA-PKcs's place. Comai proposes that the displacement of DNA-PKcs by WRN might act as a switch to entice a different set of repair machinery to the marred site.

It's unclear how to reconcile the observations of the two groups and the previous work. Although researchers have scrutinized WRN's behavior in a test tube, they know little about its activity in animals--or about how lack of the protein results in accelerated aging. But the new findings bolster the idea that WRN's interplay with Ku and DNA-PKcs governs its function.

--R. John Davenport

P. Karmakar, J. Piotrowski, R. M. Brosh Jr., J. A. Sommers, S. P. Lees Miller, W.-H. Cheng, C. M. Snowdon, D. A. Ramsden, V. A. Bohr, Werner protein is a target of DNA-PK in vivo and in vitro and its catalytic activities are regulated by phosphorylation. J. Biol. Chem., 11 March 2002 [e-pub ahead of print]. [Abstract] [Full Text]

Further Reading

  • S. M. Yannone, S. Roy, D. W. Chan, M. B. Murphy, S. Huang, J. Campisi, D. J. Chen, Werner syndrome protein is regulated and phosphorylated by DNA-dependent protein kinase. J. Biol. Chem. 276, 38242-38248 (2001). [Abstract] [Full Text]

Citation: R. J. Davenport, Twisted Logic: Discoveries tangle Werner syndrome helicase story (Werner syndrome). Science's SAGE KE (27 March 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/12/nw40








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