Revealing the secrets of WRN 23/4/06. By DOE/Lawrence Berkeley National Laboratory The unique protein responsible for Werner's syndrome.

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 ageing and cancer.

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 ageing. Beginning in their twenties, victims may become afflicted with cataracts, hair loss, wrinkled skin, osteoporosis, arteriosclerosis and type 2 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.

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. 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.

Jeff Perry (Scripps Research Institute), Steven Yannone (Berkeley Lab) 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 are reported in the journal Nature Structural & Molecular Biology.

Structure and function

Using X-ray crystallography, the researchers determined how WRN-exo was folded. The fold structure revealed that WRN-exo belongs to a family of nucleases involved in maintaining genomic integrity, the DnaQ family, which has a long evolutionary history and is found in archaea, bacteria and viruses, as well as higher plants and animals. Indeed, WRN-exo is the first member of the family whose structure has been determined in humans.

The structure of the larger WRN protein is known to be built from several individual copies of WRN. To determine how individual WRN-exo units might work together as a complex, the researchers borrowed a similarly folded DnaQ protein from a plant, Arabidopsis thaliana ('Mouse-ear cress'), and used it as a template for the likely higher-order structure. The result was a ring of six WRN exonuclease domains, just the right size to slip around a DNA helix, with their binding and catalysis sites oriented inward toward the encircled DNA.

Leading questions

Yannone is particularly intrigued by the hope of understanding why the symptoms of Werner's syndrome don't show up until early adulthood, even though WRN is a highly versatile protein that would seem to function at all stages of development: "I suspect that WRN functions in many cellular processes but is essential to only some of them - these unique functions being the key to its role in ageing."

The structure of WRN exonuclease may be a clue to its selectivity. WRN nuclease is similar to the proofreading domain of the DnaQ family of DNA polymerases, but the nature of WRN's interactions with other key proteins may dictate a more complex, higher-order editing role in maintaining the human genome.

"The modularity of WRN-exo is one of the things that's exciting to me," says John Tainer. "There are some 30 000 human genes, but the connections among them are not like a wiring diagram - they're more like the way an airline connects its routes, with many pathways going through a few major hubs. WRN is one of those hubs."

Adapted from a news release by DOE/Lawrence Berkeley National Laboratory.

Further reading

Perry JJ, et al. WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing. Nat Struct Mol Biol. 2006 Apr 23. Abstract