The long term goal of this research is to understand how nucleic acids are oxidatively damaged, and to use this knowledge to design new therapeutic candidates and research tools. Nucleic acid oxidation is important in the etiology and treatment of disease. For instance, ionizing radiation causes cancer and destroys tumor cells by damaging DNA. Nucleic acid oxidation is also an important biotechnology tool. For instance, hydroxyl radical cleavage is useful for determining RNA structure and folding dynamics, as well as for determining nucleic acid binding interactions;These studies will be accomplished using synthetic and physical organic chemistry, biochemistry, as well as molecular and cellular biology. We pursue a complementary two-fold experimental approach. We study reaction mechanism by designing molecules that enable us to independently generate reactive intermediates at defined sites in oligonucleotides. In addition, when our mechanistic studies provide the appropriate impetus, we synthesize molecules that capitalize upon these discoveries. The proposed research encompasses the following goals: 1. Design and study in vitro and in cells of mechanism-based radiosensitizing agents that produce DNA interstrand cross-links. 2. Determine the repair of a novel family of interstrand cross-links in vitro and in E. coli. 3. Examine the reactivity of the radical resulting from C5'-hydrogen atom abstraction in DNA. This radical is produced by a variety of antitumor agents and is a major source of cleavage resulting from reaction with hydroxyl radical. 4. Explore the ability of nucleobase radical adducts in RNA to produce direct strand breaks. 5. Design molecules that will exploit electron transfer in DNA as a means for producing interstrand cross- links. Relevance to public health: Oxidative nucleic acid damage plays an important role in aging, as well as the etiology and treatment of genetic diseases, such as cancer. Nucleic acid oxidation is also an invaluable research tool in biotechnology (e.g. probing nucleic acid structure and folding dynamics), which is in turn used to study human disease. Hence, this fundamental research is valuable to understanding the etiology and treatment of diseases such as cancer. Furthermore, the application of the knowledge gleaned from this research provides the starting point for potentially new therapeutics and research tools.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054996-12
Application #
7742606
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Fabian, Miles
Project Start
1997-07-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
12
Fiscal Year
2010
Total Cost
$333,294
Indirect Cost
Name
Johns Hopkins University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sun, Huabing; Taverna Porro, Marisa L; Greenberg, Marc M (2017) Independent Generation and Reactivity of Thymidine Radical Cations. J Org Chem 82:11072-11083
Zheng, Liwei; Griesser, Markus; Pratt, Derek A et al. (2017) Aminyl Radical Generation via Tandem Norrish Type I Photocleavage, ?-Fragmentation: Independent Generation and Reactivity of the 2'-Deoxyadenosin- N6-yl Radical. J Org Chem 82:3571-3580
Zheng, Liwei; Lin, Lu; Qu, Ke et al. (2017) Independent Photochemical Generation and Reactivity of Nitrogen-Centered Purine Nucleoside Radicals from Hydrazines. Org Lett 19:6444-6447
Zheng, Liwei; Greenberg, Marc M (2017) DNA Damage Emanating From a Neutral Purine Radical Reveals the Sequence Dependent Convergence of the Direct and Indirect Effects of ?-Radiolysis. J Am Chem Soc 139:17751-17754
Cheng, Bokun; Zhou, Qingxuan; Weng, Liwei et al. (2017) Identification of proximal sites for unwound DNA substrate in Escherichia coli topoisomerase I with oxidative crosslinking. FEBS Lett 591:28-38
Paul, Rakesh; Greenberg, Marc M (2016) Mechanistic Studies on RNA Strand Scission from a C2'-Radical. J Org Chem 81:9199-9205
Greenberg, Marc M (2016) Reactivity of Nucleic Acid Radicals. Adv Phys Org Chem 50:119-202
Greenberg, Marc M (2016) Pyrimidine Nucleobase Radical Reactivity in DNA and RNA. Radiat Phys Chem Oxf Engl 1993 128:82-91
Pidugu, Lakshmi S; Flowers, Joshua W; Coey, Christopher T et al. (2016) Structural Basis for Excision of 5-Formylcytosine by Thymine DNA Glycosylase. Biochemistry 55:6205-6208
Paul, Rakesh; Greenberg, Marc M (2015) Rapid RNA strand scission following C2'-hydrogen atom abstraction. J Am Chem Soc 137:596-9

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