Davis, William B.
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Research Interests
Oxidative stress has been shown to contribute to aging and many disease etiologies, including diabetes, cancer, and atherosclerosis. The Davis Lab is interested in understanding how genomic and mitochondrial DNA are impacted by exogenous and endogenous oxidants. Our research encompasses questions ranging from 1) the initiation of DNA oxidative damage to 2) cellular damage repair mechanisms and 3) the consequences of DNA oxidative lesions on cellular processes like transcription and chromatin remodeling. Researchers in the Davis lab learn and apply techniques from Biochemistry, Biophysics, Molecular Biology, Quantum Chemistry, and Bioorganic Chemistry. Our current research focuses on the following areas.

1. DNA CHARGE TRANSPORT

Long-range DNA charge transport (CT) is one manifestation of oxidative stress that we are interested in. In this process, a one electron oxidation event leads to the formation of a guanine radical cation (G ·+). After formation, G ·+ has several fates available to it including reactions with solvent or other species like O 2 or superoxide to yield, among others, mutagenic, two electron oxidation products of guanine like 8-oxoguanine (8OG) and Formamidopyrimidine (FAPY-G). Competing with these trapping reactions are electron transfer reactions from nearby guanines to the initially oxidized nucleobase. These so called hole transfer reactions result in the propagation of an oxidized lesion (G ·+) long distances (> 200 Å) away from the site of initial damage. While much is understood about CT in naked DNA, we are currently investigating how the DNA-protein complexes found throughout the eukaryotic cell affect i) the dynamics of hole transport in DNA, and ii) the observed distribution and types of oxidative damage observed.

Our current DNA-protein complex of interest is the nucleosome core particle (NCP), the fundamental building block of chromatin. Thus far we have discovered that specific DNA-histone contacts significantly affect DNA CT. In addition to an altered guanine damage distribution, DNA CT in a NCP gives rise to DNA-protein cross-links (DPCs) between the packaged DNA and core histone proteins. Current studies in our laboratory focus on i) a molecular and structural understanding of the chemistry linking DNA CT to DPC formation in the NCP and other DNA-protein complexes, ii) in vivo interrogation of DNA CT in eukaryotic cells and nuclei, and iii) the effects of DPC formation on fundamental cellular processes such as transcription, replication, and chromatin remodeling.

To further our understanding of the dynamics of DNA CT in DNA-protein complexes, we are currently collaborating with Dr. Alexander Voityuk (IRCEA, Spain) on a project applying quantum chemical calculations and molecular dynamics simulations to understand how changes in DNA structure and local environment in DNA-protein complexes perturb DNA CT.

2. DNA REPAIR IN CHROMATIN

We are currently focusing on two aspects of DNA repair reactions in chromatin. Both utilize the NCP as our chromatin model; the first is concerned with the dynamics of BER on oxidative lesions like 8OG located in NCPs, and the second series of studies focus on delineating the identity and dynamics of the DNA repair pathways functional on DPCs formed in NCPs and higher chromatin structures.

3. PAR AND ITS ROLES IN DNA REPAIR

A third project in the Davis lab focuses on Poly(ADP-ribose), a nucleic acid polymer whose roles in the cell are of intense current interest. The addition of polymeric forms of ADP-ribose to proteins by enzymes like PARP-1 is an event which has been shown to influence many intracellular events. We are interested in delineating the roles that ADP-ribosylation reactions play in DNA repair, and in particular their influence on BER. We have recently discovered that many of the BER glycosylases which repair oxidative lesions bind to PAR in vitro, and therefore they join a growing list of proteins including the core histones and P53 which possess the ability to bind to PAR. The consequences of the interaction between PAR and BER glycosylases on DNA repair reactions and other cellular processes are currently under investigation in our laboratory using a combination of in vitro and in vivo studies.

Publications
Bjorklund, C.C., Davis, William B. “ Stable DNA-Protein Cross-links are Products of DNA Charge Transport in the Nucleosome Core Particle”Accepted for publication, Biochemistry, May 2007. 

Voityuk, A.A., Davis, William B. “Hole Transfer Energetics in Structurally Distorted DNA: The Nucleosome Core Particle” Revised for Publication, J. Phys. Chem. B., 2007, 111, 2976-85.

Bjorklund, C.C., Davis, William B. “Attenuation of DNA Charge Transfer by Compaction into a Nucleosome Core Particle.” Nucleic Acids Res. 2006, 34, 1836-1846.

Weicherding, D., Davis, William B., Hess, S., von Feilitzsch, T., Michel-Beyerle, M.E., Diederichsen, U. “ Femtosecond time-resolved guanine oxidation in acridine modi fied alanyl peptide nucleic acids.“ Bioorganic Med. Chem. Lett.2004, 14, 1629–1632.

Hess, S., Gotz, M., Davis, William B., Michel-Beyerle M.E. “On the apparently anomalous distance dependence of charge-transfer rates in 9-amino-6-chloro-2-methoxyacridine-modified DNA,” J. Am. Chem. Soc. 2001, 123, 10046-10055.