Research Notes

Same Enzyme Repairs DNA, Repels Pathogens An enzyme involved in genome defense has been shown to attack invading pathogens (W-M. Chu et al., "DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA," Cell, 103:909-18, Dec. 8, 2000). Researchers already knew that DNA-dependent protein kinase (DNA-PK) in the nucleus repairs DNA double-stranded breaks created by radiation, but the role of DNA-PK in the cytoplasm was unknown. Testing DNA immunostimulatory (ISS) sequences in mice bred without DNA-PK, scientists at University of California, San Diego, discovered that the enzyme is the key to activating transcription factor NF-*B, leading to the activation of pathogen-attacking macrophages. Mice bred without the DNA-PK failed to mount an immune response against bacteria, viruses, and toxins. The scientists had theorized that the human body's innate immunity, the body's first-line defense system, must react like lower organisms such as bacteria to invading pathogens. But humans don't have restrictive enzymes like bacteria. "So we looked for something similar that had immunostimulatory properties," said lead author Eyal Raz. "And here is where the intriguing story of DNA-PK came in." The findings hold potential therapeutic applications. Now that the enzyme's dual role is known, it may be possible to develop stimulants of the immune response to activate the body's DNA repair, Raz said. It may also be possible to treat DNA instability caused by radiation-induced injuries or mutations caused by the side effects of cytotoxic cancer medications, he said. "Science is finding more and more multiple roles for different enzymes," Raz said. "Our role is to make sense of the information." --Jennifer Fisher Wilson Cancer causing protein complex crystallized In crystallizing a protein complex implicated in cell metastasis, scientists exposed on an atomic level what makes cancer cells invasive. Crystallation of the three-dimensional structure of Rho-family G protein Rac1 (bound to its activator, Tiam1) was necessary to understand exactly how Rho family G proteins--which normally help regulate such functions as cell shape, division, and proliferation--become activated, said John Sondek, assistant professor of pharmacology at UNCUniversity of North Carolina, Chapel Hill School of Medicine. The research, published recently in Nature, may be useful in developing therapies that inhibit cancer cells from spreading (D.K. Worthylake et al., "Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1, Nature, 408:682-8, 2000.). Sondek and colleagues will use the crystal structure to rationalize positive hits and subsequently guide more directed screening. "Right now, we are pursuing high throughput screening for compounds that inhibit the activation process," Sondek said. Activation of G proteins depends on the molecular signal they receive from other proteins, guanine nucleotide exchange factors (GEFs) like Tiam 1. Malignancies occur when G-proteins are perpetually activated. When Tiam1 is overexpressed, for example, it causes invasion and spreading of a lymphoma that is not normally invasive. Malignant growth occurs upon either overexpression or N-terminal truncation of Tiam1. Truncation and aberrant expression is typically associated with chromosomal rearrangements, Sondek said. Many GEFs related to an exchange factor originally characterized in a diffuse B-cell lymphoma have been isolated as oncogenes upon N-terminal truncation, and this truncation removes internal inhibitory constraints within the GEF and constitutive exchange activity, he added. The Tiam1/Rac1 structure is one aspect of a large collaborative effort at UNC Chapel Hill to understand the structural biology of Rho G-protein signaling and Ras (a common oncogene with similarities to the Rho) G-protein signaling. The goal, Sondek said, is to couple this information with the in vivo consequences of G-protein signaling, and to use this information to disrupt signaling processes in cells and link Rho and Ras signaling pathways through Tiam1 and other Dbl-related GEFs. --Jennifer Fisher Wilson Fighting Alzheimer's Disease Recent papers published in Science and Nature report potentially important steps toward improved diagnosis and treatment of Alzheimer's disease (AD). Three independent groups, published in Science, identified similar regions of chromosome 10 believed to contain one or more genes associated with late-onset AD,1-3 a much rarer find than loci involved in early-onset AD. Although chromosome 10 was thought to harbor an AD-associated gene for some time, these papers present the first statistically significant evidence that such a gene exists. In an AD first, one reserach team used a surrogate marker for the disease to map to the culprit chromosome 10 region.2 Much like using cholesterol levels to detect heart disease, researchers based their mapping on subjects' high plasma levels of amyloid-ß (Aß), the peptide that accumulates in AD brains to form neuron-suffocating plaques. Investigators suspect that the as-yet unidentified chromosome 10 AD gene actually influences the level of Aß in the brains of AD patients. The degree of diagnostic usefulness of the chromosome 10 locus still remains unclear. Related research in three Nature papers suggests, for the first time, that reducing Aß accumulation actually improves cognitive performance in mice.4-6 An AD vaccine in development has previously been shown to halt Aß plaque formation in mice.7 Researchers have now shown that mice inoculated with the vaccine not only show reduced Aß deposits, but perform better on spatial memory tests.4,5 An additional study shows that, using a new memory test, researchers can distinguish plaque-invoked from age-related memory deficits in mice.6 All of the results further strengthen the so-called Aß hypothesis, which holds that Aß plaques are a causative agent and not just a byproduct of AD. "This draws a link between the peptide and cognitive change," says University of Toronto associate professor of pathobiology, David Westaway, a senior author on one of the papers.4 "That link was always implied but was never really there in a tractable system you could do experiments on." --Eugene Russo References 1. L. Bertram et al., "Evidence for Genetic Linkage of Alzheimer's Disease to Chromosome 10q," Science, 290:2302-3, Dec. 22, 2000. 2. N. Ertekin-Taner et al., "Linkage of plasma Aß42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees," Science, 290:2303-4, Dec. 22, 2000. 3. A. Myers et al., "Susceptibility locus for Alzheimer's disease on chromosome 10," Science, 290:2304-5, Dec. 22, 2000. 4. C. Janus et al., "Aß peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease," Nature, 408:979-82, Dec. 21, 2000. 5. D. Morgan et al., "Aß peptide vaccination prevents memory loss in an animal model of Alzheimer's disease," Nature, 408:982-85, Dec. 21, 2000. 6. G. Chen et al., "A learning deficit related to age and ß-amyloid plaques in a mouse model of Alzheimer's disease," Nature, 408:975-79, Dec. 21, 2000. 7. E. Russo, "Nothing to sniff at," The Scientist 14[20]:17, Oct. 16, 2000.

Research Notes

Same Enzyme Repairs DNA, Repels Pathogens

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