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Environmental Health Sciences CenterLeona D Samson, Ph.D. Project DescriptionThe overall focus of the NIEHS Center for Environmental Health Sciences (CEHS) at the Massachusetts Institute of Technology (MIT) is to understand how toxic environmental agents perturb biological systems and to determine how such perturbations may affect human health. Founded in the early 1970s, the CEHS is now directed by Leona Samson and Peter Dedon. The current CEHS membership consists of 32 faculty members derived from a total of 8 MIT departments (in the Schools of Science and Engineering), plus three Departments in the Harvard School of Public Health (HSPH) and one in the Harvard Medical School (HMS). The MIT departments are Biology, Chemistry, Biological Engineering, Chemical Engineering, Civil & Environmental Engineering, Mechanical Engineering, Nuclear Engineering, Electrical Engineering & Computer Science; the HSPH departments are Epidemiology, Nutrition and Environmental Health. The current Research Cores, each led by an MIT Professor, are (i) the Mutation and Cancer Research Core (led by Peter Dedon); (ii) the Bioengineering for Toxicology Research Core (led by Linda Griffith); and (iii) the Environmental Systems and Health Research Core (led by David Schauer). The current Facilities Cores are (i) the Bioanalytical Core (led by John Wishnok), (ii) the Genomics and Bioinformatics Core (led by Peter Sorger) and (iii) the Animal Models and Pathology Core (led by James Fox). The services available through the three Facilities Cores include sophisticated mass spectrometry, accelerator mass spectrometry, chromatography, transcriptional profiling and computational analysis of such data, transgenic and knock out animal production, pathology services, and state-of the-art microscopy and imaging. Other units include the Administrative Core, the Pilot Project Program and the Community Outreach and Education Program (COEP). The Center also co-sponsors three departmental seminar series, and sponsors a CEHS member seminar series, an annual retreat and several other mechanisms designed to nurture interactions among CEHS members and to promote the activities of the CEHS and an awareness of environmental health science in the MIT community. Project HighlightsA multi-lab interdisciplinary collaborative effort in 2005 led the Essigmann, Samson and Drennan laboratories to the discovery that 1,N6-ethenoadenine and related exocyclic alkene-DNA adducts are removed from DNA by E. coli AlkB by a unique mechanism involving alkene epoxidation followed by hydration and release of the glycol as glyoxal. Following on this observation in 2006, the Essigmann and Drennan labs found that the related alkane adduct, 1,N6-ethanoadenine, is repaired by another novel route. Oxidation by AlkB in this case results in hydroxylation of the saturated exocyclic hydrocarbon bridge. The hydroxyl group then rearranges and is released from the N1 atom of adenine, while retaining DNA linkage at the exocyclic N6. Before AlkB treatment the ethano adenine adduct is exceptionally lethal in vivo. After the reaction, the N6 mono-adduct is readily bypassed in vivo, leading to much reduced toxicity. This is the first time a repair enzyme has been shown to rearrange an adduct in an apparent attempt to reduce toxicity. Frick, L.E., Delaney, J.C., Wong, C, Drennan, C.L., and J.M. Essigmann. Alleviation of 1,N6-ethanoadenine genotoxicity by the Escherichia coli adaptive response protein AlkB. Proc. Natl. Acad. Sci. (USA). 104: (3):755-60, 2007.
Margolin, Y., Cloutier, J.-F., Shafirovich, V., Geacintov, N. and Dedon, P.C.. Paradoxical hotspots for guanine oxidation by a chemical mediator of inflammation. Nature Chem. Biol., 2: 365-366, 2006. This work was featured on the cover of Nature Chemical Biology and in a News and Views Commentary by Cadet, Douki & Ravant on page 348 of the same issue. Community Outreach and EducationThe CEHS Community Outreach and Education Program in collaboration with the MIT Museum through pilot project funding developed an interactive exhibit entitled "The Cell is a Molecular Machine". This exhibit is designed to help visitors learn what DNA does in the cell, and how DNA relates to health issues such as cancer using LEGO molecules. The gallery space is unique, serving both the usual walk-in visitor as well as groups of people in a facilitated, hands-on program. In addition is the development of several original multimedia pieces for the Learning Lab. There is terrific material in progress (Dec 2006) - captivating LEGO DNA animations on DVDs; candid films of CEHS researcher describing their work; and cool computer programs that explain breakthroughs in environmental health. It is anticipated that these multimedia presentations will further help to attract and educate visitors. |
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The Dedon lab recently published a paper describing an apparent paradox in the selection of DNA targets by oxidizing agents. It has long been assumed that DNA oxidants selectively attack the guanine bases in sequence contexts surrounded by other guanines. This behavior has been attributed to migration of the initially formed radical cation to a nearby guanine with the lowest ionization potential, with charge migration terminated by trapping and final product formation. Support for this model came from observations of an inverse correlation between ionization potentials for guanines in different sequence contexts and the reactivity of the guanines toward riboflavin-mediated photo-oxidation. This observation led to the general conclusion that all DNA oxidants would produce high levels of damage at the most readily oxidized guanines as a result of charge migration to the lowest energy hole trap. Contrary to this model, the Dedon group observed a different behavior with nitrosoperoxycarbonate (ONOOCO2-), one of the chemical mediators of inflammation arising from macrophage-generated nitric oxide. They observed that this oxidant selectively damaged the guanine with the highest oxidation potential in short oligonucleotides and in genomic DNA. These results explain the observed positive correlation between mutation frequency and the quantity of DNA damage produced by ONOOCO2-, and reveal that current models of guanine oxidation and charge transfer in DNA need to be revised if we are to predict the location and chemistry of mutagenic DNA oxidation in the genome. 
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