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News

The unique protein responsible for Werner's Syndrome Aids Research in cancer and aging

DOE/Lawrence Berkeley National Lab : 04 July, 2006  (Company News)
A team of scientists from Lawrence Berkeley National Laboratory and the Scripps Research Institute has determined the crystal structure and molecular mechanisms of a key part of WRN, a protein that protects humans from premature aging and cancer.
The fold structure of the WRN exonuclease domain, with alpha helices (blue), beta strands (green), and loops (brown). The active-site amino-acid residues are at center (yellow), showing oxygen atoms (red) and two manganese ions (magenta).

When the gene for WRN is defective the result is Werner's syndrome, a rare inherited disease that shows no symptoms until puberty but soon causes rapid aging. Beginning in their twenties, victims may become afflicted with cataracts, hair loss, wrinkled skin, osteoporosis, arteriosclerosis, and type II diabetes; many patients contract cancer, and most die by the age of 50. Understanding how the WRN protein normally works to maintain genomic integrity could lead to new forms of treatment for cancer and age-related pathologies.

'One reason we are particularly interested in WRN is because Werner's syndrome is unusual among premature-aging diseases, in that children are born normal and show no signs of disease until early adulthood,' says Steven Yannone of Berkeley Lab's Life Sciences Division. 'This gives us a better chance of clearly separating defects in development from aging.'

'We wanted to study the protein itself because it is unique,' says Jeff Perry of the Scripps Research Institute's Department of Molecular Biology and Skaggs Institute for Chemical Biology, formerly of Berkeley Lab, who led the research with Yannone. 'WRN belongs to a family of enzymes called RecQ helicases', of which there are five in the human genome, performing important functions in DNA replication, recombination, and repair, 'but in this family, only WRN has coupled a helicase function and a nuclease function within the same protein.'

Helicases open up the double helix of DNA, while nucleases degrade one or both of the DNA chains; both operations are critical to repairing errors and proofreading DNA sequences. One part of WRN is an exonuclease, which starts working from the end of a DNA strand. Perry and Yannone and their colleagues determined the structure of the WRN exonuclease domain and showed how the enzyme may function in a series of specific DNA repair events. Their findings will soon appear in Nature Structural & Molecular Biology and are now available online.

All the members of the research team were participants in the SBDR program (Structural Cell Biology of DNA Repair Machines) sponsored by the National Cancer Institute. John Tainer, a professor at Scripps Research, member of the Skaggs Institute for Chemical Biology, and a visiting scientist at Berkeley Lab, is SBDR's principal investigator. Co-principal investigator is Priscilla Cooper, head of the Department of Molecular Biology in Berkeley Lab's Life Sciences Division.

Tainer says, 'The exonuclease domain of the WRN protein is a prime example of what we in SBDR call 'master keys,' structures that open doors to lots of different repair pathways. Among other things, WRN is involved in repairing double-strand breaks, single-strand breaks, replication forks and junctions, even DNA-RNA duplexes. How does one protein know how to interact in so many different processes? If we can understand how this unique protein works, we'll have a key to how all these pathways work in human beings.'

Cooper says, 'Understanding the relationship between the structure of WRN and how it performs its multiple functions to prevent aging and cancer is a perfect example of the kind of problem we designed the SBDR program to solve. With 21 investigators in 15 institutions, SBDR's goal is to gain fundamental insights into the molecular machines that maintain genomic integrity, by applying a range of experimental techniques.'

Other members of the SBDR team who researched WRN were Lauren Holden and Chiharu Hitomi of Scripps Research, Aroumougame Asaithamby and David Chen of the University of Texas Southwestern Medical Center, and Seungil Han of Pfizer, Inc. Asaithamby, Han, and Chen are former members of Berkeley Lab; Chen is a senior member of the SBDR program.
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