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Photo of Dr. David M. Wilson, III David M. Wilson, III, Ph.D., Senior Investigator
Repair of Endogenous DNA Damage Section
Laboratory of Molecular Gerontology

Phone: 410-558-8153
Fax: 410-558-8157
Biography:  Dr. Wilson received a Bachelor of Arts degree in both Biology and Political Science from Bucknell University in 1989. He completed his Ph.D. work in 1993 at Loyola University of Chicago, Stritch School of Medicine, as part of the Molecular Biology Program. Dr. Wilson performed his postdoctoral research training at the Harvard School of Public Health until 1997, when he became a Senior Biomedical Scientist at Lawrence Livermore National Laboratory in the Biology and Biotechnology Research Program. For part of the time while at Livermore, he was an adjunct faculty member in the Radiation Oncology Department at the University of California Cancer Center, Sacramento. Dr. Wilson started at NIA in 2002 and was converted to a tenured investigator in 2008.

Research Topics

Reactive oxygen species are formed as by-products of mitochondrial oxidative phosphorylation or after exposure to environmental agents.  These products react with lipids, proteins and nucleic acids, and contribute to aging and age-related disease by promoting the gradual accumulation of macromolecular damage and consequent cellular dysfunction or cell death.  Oxidative DNA damage, which includes non-bulky (e.g., 8-oxoguanine) and bulky (e.g., cyclopurines) base modifications, abasic sites, non-conventional single-strand breaks, protein-DNA adducts and intra/interstrand crosslinks, poses a mutagenic and cytotoxic challenge to the cell.  My laboratory focuses on elucidating the molecular pathways for the repair of endogenous DNA damage, with an eye towards defining the contribution of specific core and auxiliary base excision repair (BER) proteins to disease manifestation, therapeutic agent responsiveness, and aging.

Delineate the precise biological contribution of the different functions of APE1.  APE1 is the major human AP endonuclease, and in this capacity, operates centrally in the BER process.  The protein also exhibits 3’ to 5’ exonuclease, 3’-phosphodiesterase, RNA cleavage, and base damage-specific nuclease activities.  In addition, APE1 possesses the ability to stimulate the DNA binding activity of several transcriptional regulators (e.g., Fos/Jun, p53 and NF-kB) via a redox mechanism.  We hypothesize that the different functions of APE1 contribute distinctly to various cellular end-points, such as viability and the DNA damage response.  Towards determining the precise contribution of the different functions of APE1, we have established gene-targeting (knock-out and knock-in) techniques for human cells.  In addition, we are developing small molecule probes to complement the proposed genetic experiments to define the biological roles of specific APE1 activities.  Finally, we are exploring the role of APE1, and BER more generally, in cellular senescence, a phenomenon associated with aging.
Determine the role of BER capacity in age-related disease susceptibility.  BER is the major mechanism for dealing with most spontaneous forms of DNA damage, and deletion of a core component, such as APE1, leads to embryonic/post-natal lethality in mice. Defects in certain BER participants are also genetically linked to cancer predisposition, neurological dysfunction and immunodeficiency. We hypothesize that subtle defects in overall BER capacity will determine susceptibility to age-related disease, particularly in the face of a relevant environmental exposure. To test this hypothesis, we are developing a series of high-throughput methods to assess BER pathway efficiency that will be applied to future association studies. In addition, we are examining the impact of amino acid sequence variation on the biochemical and biological functions of specific BER proteins, as such variants may represent disease susceptibility or disease-promoting factors.
Define the molecular contributions of the Cockayne syndrome (CS) proteins to the repair of endogenous DNA damage.  CS is an autosomal recessive disorder, characterized by premature aging symptoms, growth failure, neurological abnormalities, and cutaneous photosensitivity, but no increased cancer incidence. We hypothesize that at least a subset of the CS pathologies arises from a defect in the repair of endogenous DNA damage, particularly transcription blocking lesions. We are therefore delineating the molecular roles of the CS proteins in DNA interstrand crosslink repair in both cycling and non-cycling cells using biochemical and cell-based strategies. We have also begun to examine whether altered function CS alleles exist that contribute to age-related pathologies within the general population.
  • PubMed: Search for listing of Dr. Wilson's publications.
Photo of Dr.  David Wilson and members of the Repair of Endogenous DNA Damage Section
Repair of Endogenous DNA Damage Section (left to right): Royce Hamilton, Post-Bac, Rachel Abbotts, Post-Doc, Boris Brennerman, Post-Bac, Teruaki Iyama, Post-Doc, Jennifer Illuzzi, Post-Doc, David M. Wilson, Senior Investigator, Daniel R. McNeill, Biologist
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Updated: Wednesday July 16, 2014