Sci. Aging Knowl. Environ., 8 October 2003
Vol. 2003, Issue 40, p. nw137
[DOI: 10.1126/sageke.2003.40.nw137]


Portrait of DNA's Protector

Researchers take first close-up of protein that stabilizes chromosomes

Mitch Leslie;2003/40/nw137

Key Words: Rothmund-Thompson syndrome • missense mutation • SF2 helicase • topoisomerase III

Cells can't stash their DNA in a lead-lined safe, but they deploy other defenses to protect their genetic material from damage that provokes cancer. A new study provides the first detailed picture of an enzyme that forestalls DNA injuries. The findings could help researchers uncover how this protein shields genes; the authors hypothesize that it serves as an early warning system for DNA-damaging conditions.

RecQ helicase belongs to an enigmatic clan of proteins that peel apart the double helix. Creatures from bacteria to humans make the proteins, whose jobs involve the three Rs: repair, replication, and recombination (swapping DNA between chromosomes). However, scientists don't know how the proteins accomplish any of these functions. Rare disorders have furnished some clues; glitches in two human versions of RecQ underlie Bloom syndrome and Werner syndrome (see Fry Review). Bloom syndrome patients are abnormally short and hypersensitive to the sun; people with Werner syndrome suffer symptoms of premature aging, including gray hair, cataracts, and atherosclerosis. Both disorders bring heightened susceptibility to tumors and fragile chromosomes that easily break and lose pieces--the kind of damage often seen in cancer cells. That similarity suggests that the proteins help fortify DNA and fend off cancer, but researchers don't know how. One missing piece of information is a map of the protein's three-dimensional structure.

To fill that gap, structural biochemist James Keck of the University of Wisconsin, Madison, and colleagues analyzed RecQ from the bacterium Escherichia coli, which produces a small version that is easy to work with and shares many similarities with the human forms. The team used a technique called x-ray crystallography to determine the structure of the protein's core, which performs most of its tasks. They identified two DNA-grasping regions, suggesting that the strands wrap around the protein's middle like a belt, and they spotted a section where zinc ions attach. Although the human protein that goes awry in Bloom syndrome isn't identical to RecQ, the results suggest how particular faults in that protein spur the disorder. Some mutations in the Bloom syndrome gene change the identities of two amino acids in the zinc-binding segment, and Keck's structure provides a physical picture of how the alterations could rebuff zinc, possibly distorting and disabling the protein. The researchers speculate that the zinc-grabbing region normally senses rising amounts of oxidants and flips on the protein when DNA is in peril. "Why wait for damage when the protein can sense potentially damaging conditions in cells?" Keck says. Cells from Bloom patients are awash with oxidants, but their proteins wouldn't be able to sense the excess and respond, he proposes.

Having a detailed portrait of the protein is big step forward, says biochemist David Orren of the University of Kentucky Chandler Medical Center in Lexington. "It gives us a framework for trying to understand how these proteins work to maintain the genome." Molecular biologist Nancy Maizels of the University of Washington, Seattle, calls the study "a significant achievement" and says it will guide researchers as they determine how different parts of the molecule work and how it cooperates with other proteins to keep DNA shipshape. That approach might reveal how cells shelter their DNA without locking it away.

--Mitch Leslie

October 8, 2003
  1. D. A. Bernstein, M. C. Zittel, J. L. Keck, High-resolution structure of the E. coli RecQ helicase catalytic core. EMBO J. 22, 4910-4921 (2003). [CrossRef][Medline]
Citation: M. Leslie, Portrait of DNA's Protector. Sci. SAGE KE 2003 (40), nw137 (2003).

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