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Intramural Papers of the Month

By Eddy Ball
July 2007

Enzyme Linked to Oxidative Damage in Huntington's Disease

A team of researchers from NIEHS, Mayo Clinic and Foundation, and the University of Oslo have demonstrated in vivo the role of a base excision repair (BER) enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1), in triggering the age-dependent somatic mutation associated with Huntington's disease (HD) that leads to progressive toxicity in somatic cells. In an NIH Intramural Program-supported study published in the May 24 issue of Nature, the scientists described a "toxic oxidation" model in which the enzyme initiates a process that leads to increasing frequency of an error in the BER of single-strand breaks (SSB) in DNA known as CAG trinucleotide expansion.

The team used transgenic male mice and female partners lacking one of the glycosylases and their litters, which had been bred until they were homozygous knockouts, to generate in vivo data for the study. They investigated the correlation of CAG expansion with DNA oxidation, normal repair of SSB, and the presence or absence of OGG1. They also performed parallel experiments in vitro with human HD fibroblasts and lymphoblasts.

The researchers discovered an "unexpected specificity for OGG1" in triggering CAG expansion in HD in vivo. That insight into the mechanism, they concluded, may have "general relevance to late onset neurodegeneration" in other conditions as well.

Citation: Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT. 2007. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447(7143):447-452. doi:10.1038/nature05720.

Carbonated Beverages and Risk for Chronic Kidney Disease

In an Intramural Research Program-funded study published in the July issue of Epidemiology, NIEHS Epidemiology Branch investigators reported a two-fold risk of kidney disease among subjects who reported drinking two or more glasses of cola a day. The scientists speculated that the use of phosphoric acid in the production of cola beverages may account for the significant association, which was not found in non-cola carbonated beverages.

The researchers collected data through telephone interviews with subjects or proxy respondents for 465 case subjects who had been newly diagnosed with kidney disease at four North Carolina hospitals between September 1980 and August 1982. The investigators also interviewed 467 NC residents without a history of kidney disease. The researchers found that the more colas a person reported drinking, the greater the risk of kidney disease.

Although the study had several limitations, including reliance on self-reporting, the authors were careful to control for confounding factors. In light of the rising incidence and costs of chronic kidney disease, which now affects over 20 million adults in the U.S., the authors concluded, "Our preliminary result of an association... deserves to be explored in more detailed studies."

Citation: Saldana TM, Basso O, Darden R, Sandler DP. 2007. Carbonated Beverages and Chronic Kidney Disease. Epidemiology 18(4):501-506.

RNA Direct Transfer of Genetic Information

A team of researchers in the NIEHS Laboratory of Molecular Genetics has published data providing evidence demonstrating that RNA can directly serve as a template in the repair of chromosomal DNA lesions in the yeast Saccharomyces cerevisiae. Their intramural research funded study, which appeared in the May 17 issue of Nature, significantly expanded previous research findings that had demonstrated mediation of recombination by RNA, but only indirectly through a complementary DNA intermediate.

The scientists induced DNA damage in the form of a unique double-strand break (DSB), which was then targeted with a type of nucleic acid segment, known as a single-strand oligonucleotide, to repair the break. These experiments were performed in a carefully controlled environment to exclude the possibility that DNA contamination might be responsible for the transfer of genetic information. The team also studied DNA synthesis reactions with DNA polymerase enzymes from S. cerevisiae that are candidates in the DNA repair process.

The researchers described their findings as generally relevant to DNA repair since much of the genome of any organism is involved in synthesizing RNA, which could be used in a reverse manner to repair corresponding regions of damaged chromosomes. The study also demonstrates how RNA that may be present in the mammalian mitochondrial DNA genome could be copied during replication. Suggesting translational applications of the research, the team concluded, "The ability of RNA to transfer genetic information to homologous chromosomal DNA could lead to new directions in gene targeting given that RNA can be amplified at will within cells."

Citation: Storici F, Bebenek K, Kunkel TA, Gordenin DA, Resnick MA. 2007. RNA-templated DNA repair. Nature 447(7142):338-341. doi:10.1038/nature05720.

NOTE: This paper is featured in this month's Nature top ten - a list of the ten articles most frequently downloaded from the Nature website as PDFs each preceding month. The full list for this month is at http://www.nature.com/nature/topten/index.html.

Mechanisms of Ozone-Induced Lung Injury in Mice

In the April issue of the American Journal of Respiratory and Critical Care Medicine, an NIEHS-funded team of scientists reported new discoveries about signal transduction pathways of tumor necrosis factor receptor (TNF-R)-mediated lung injury induced by ozone (O3), a principal oxidant in air pollution. Based on their previous findings from a genetic linkage analysis in which TNF has been found as a candidate susceptibility gene for pulmonary inflammation by O3, the investigators studied the roles of two pathways that serve as downstream effectors of TNF in lung injury - nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase/activator protein 1(MAPK/AP-1).

To elucidate the molecular mechanisms underlying TNF-mediated lung injury induced by O3, the researchers exposed three knock-out strains of mice and their respective wild-type mice to concentrations of O3 proportionate to exposure levels experienced by humans. Animal lungs and lung tissue were then examined for differences in histopathology, cellular inflammation and hyperpermeability, and molecular changes including DNA binding activity and mRNA abundance. The researchers were able to pinpoint which genetic profiles, and consequently which signal transduction pathways, influenced the animals' reactions to O3 exposure.

This study demonstrated that NF-κB and MAPΚ/AP-1 played important roles in O3-induced lung inflammation and injury mediated through TNF-R. The authors concluded that "the current study provided details of molecular events underlying pulmonary O3 toxicity," a potentially important advance in discovering therapeutic targets for sufferers of allergy and asthma in association with environmental O3 exposure.

Citation: Cho HY, Morgan DL, Bauer AK, Kleeberger SR. 2007. Signal transduction pathways of tumor necrosis factor--mediated lung injury induced by ozone in mice. Am J Respir Crit Care Med 175(8):829-839.



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