Marc M. Greenberg
Organic and Bioorganic Chemistry
Johns Hopkins University
New Chemistry Building 313
3400 North Charles St.
Baltimore, MD 21218
PhD - Yale University
American Cancer Society Postdoctoral Fellow - California Institute of Technology
Alfred P. Sloan Foundation Fellow - '96 -'99
As the carrier of genetic information, DNA damage and repair is important in aging and a variety of genetically based diseases, such as cancer. Certain types of modified nucleic acids are becoming increasingly important as diagnostic tools and therapeutic agents. The pivotal roles of nucleic acids (DNA, RNA) in chemistry and biology are interwoven. For instance, the reactivity of DNA with reactive oxygen species determines the types of structural modifications (lesions) formed. The interaction of DNA lesions with repair and polymerase enzymes in turn determines their biological effects. Identifying the location and level of DNA lesions in the genome may assist the diagnosis and treatment of disease.
Our research group uses organic chemistry to address questions concerning the reactivity, function, structure, and uses of nucleic acids. Examples of current projects in our group are:
• determining how nucleic acids are oxidatively damaged by synthesizing molecules (e.g. 1 and 2) that enable us to independently generate reactive intermediates at defined sites in DNA.
• elucidating the effects of specific DNA lesions (e.g. C4-AP, Fapy•dG) on the function of nucleic acids, and their structural basis.
• developing reagents that enable us to selectively detect lesions in DNA.
To bring these projects to fruition we synthesize novel molecules and study their behavior using a variety of physicochemical, biochemical, and biological techniques.
Recent accomplishments by our research group in these areas include:
• the discovery of the first example of a DNA radical that forms interstrand cross-links
• the discovery of novel pathways for DNA damage that produce tandem lesions.
• the discovery of the first example of irreversible inhibition of DNA repair by a lesion.
• the development of the first sensor for a DNA lesion other than an abasic site.
• the discovery of a novel biological effects upon replication of oxidized abasic lesions (e.g. C4-AP) in E. coli.
• the first synthesis of oligonucleotides containing formamidopyrimidine lesions (e.g. Fapy•dG) and determination of their effects on DNA repair and polymerase enzymes.