Dead Before Fifty--Damage to DNA Mounts With Loss of Repair Protein

Our DNA is the basis for every moment of our existence. Our cells have complex mechanisms for repairing incidental day-to-day damage that inevitably occurs to DNA. But what happens when the DNA repair mechanism breaks down? That is what happens in Werner's Syndrome, when the gene for the WRN helicase protein is defective, and repairs normally initiated by WRN do not take place.

This newsreport describes the work of two California research teams who have solved the crystal structure of the WRN protein.

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 (WRN-exo) 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.

....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." There is much more information from the research at the source.

There are many potential causes for aging, and we may have to study them all in depth before a truly effective rejuvenation therapy scheme can be developed that is broadly applicable to most people. Learning how to help people who suffer from diseases such as WS are the top priority. The spinoffs from such new knowledge will benefit everyone.

This link will take you to a few tutorials on DNA repair proteins. WRN is one of many repair proteins that often work in concert to repair various types of damage to DNA. This article suggests some of the complexity involved.