DNA damage causes mutation or cell death and is a contributing factor to carcinogenesis. Our laboratory has focused on DNA damage by electrophilic species generated endogenously by oxidative stress or inflammation. We are particularly interested in the lipid oxidation product, malondialdehyde (MDA), and the DNA oxidation products, base propenals. Previous work from our laboratory has provided a comprehensive inventory of adducts formed on reaction of MDA/base propenals with deoxynucleosides and DNA;demonstrated that the major adduct to deoxyguanosine (MldG) is mutagenic in bacterial and mammalian cells;revealed that MldG is repaired by nucleotide excision repair;and provided rigorous anal3^ical evidence that MldG is present endogenously in the human genome. In the most recent grant period, we have provided a detailed kinetic and structural analysis of the induction of mutations by MldG by Y-family translesion polymerases including a crystal structure of an MldG-containing template-primer bound in the active site of Dpo4;discovered that the major adduct of MDA/base propenals to deoxyadenosine, which is called OPdA, reacts with amino acids to form stable cross-links to DNA;and reported that MldG is present in the urine of healthy human subjects along with a single major metabolite, 6-oxo-MldG. These discoveries place us in an outstanding position to explore the chemical biology of DNA damage by endogenous products of oxidative stress and inflammation.
Our specific aims for the next grant period are to (1) Determine the structural and functional consequences of the interaction of template-primers containing the endogenous adducts, MldG, OPdA, and heptanone-etheno-dG with Y-family DNA polymerases;(2) Explore the chemistry of DNA-DNA and DNA-protein cross-linking mediated by the endogenous adducts, OPdA and OPdC;and (3) Develop highly sensitive and specific analytical methods for quantification of MldG and 6-oxo-MldG that will allow simultaneous monitoring of both lesions in human populations and animal models.
Cancer is caused by mutations to normal genes that regulate processes such as growth, survival, and invasion. Our laboratory discovered that DNA damage, which is a major cause of genetic mutations, can occur from normal metabolic processes such as inflammation. Since the relationship between chronic inflammation and cancer has been known for over a hundred years, our research should help to define the molecular basis for this major cause of human cancer.
|Galligan, James J; Wepy, James A; Streeter, Matthew D et al. (2018) Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks. Proc Natl Acad Sci U S A 115:9228-9233|
|Galligan, James J; Marnett, Lawrence J (2017) Histone Adduction and Its Functional Impact on Epigenetics. Chem Res Toxicol 30:376-387|
|Galligan, James J; Kingsley, Philip J; Wauchope, Orrette R et al. (2017) Quantitative Analysis and Discovery of Lysine and Arginine Modifications. Anal Chem 89:1299-1306|
|Beavers, William N; Rose, Kristie L; Galligan, James J et al. (2017) Protein Modification by Endogenously Generated Lipid Electrophiles: Mitochondria as the Source and Target. ACS Chem Biol 12:2062-2069|
|Camarillo, Jeannie M; Ullery, Jody C; Rose, Kristie L et al. (2017) Electrophilic Modification of PKM2 by 4-Hydroxynonenal and 4-Oxononenal Results in Protein Cross-Linking and Kinase Inhibition. Chem Res Toxicol 30:635-641|
|Camarillo, Jeannie M; Rose, Kristie L; Galligan, James J et al. (2016) Covalent Modification of CDK2 by 4-Hydroxynonenal as a Mechanism of Inhibition of Cell Cycle Progression. Chem Res Toxicol 29:323-32|
|Wauchope, Orrette R; Beavers, William N; Galligan, James J et al. (2015) Nuclear Oxidation of a Major Peroxidation DNA Adduct, M1dG, in the Genome. Chem Res Toxicol 28:2334-42|
|Beavers, William N; Serwa, Remigiusz; Shimozu, Yuki et al. (2014) ?-Alkynyl lipid surrogates for polyunsaturated fatty acids: free radical and enzymatic oxidations. J Am Chem Soc 136:11529-39|
|Galligan, James J; Rose, Kristie L; Beavers, William N et al. (2014) Stable histone adduction by 4-oxo-2-nonenal: a potential link between oxidative stress and epigenetics. J Am Chem Soc 136:11864-6|
|Shuck, Sarah C; Rose, Kristie L; Marnett, Lawrence J (2014) Mass spectrometric methods for the analysis of nucleoside-protein cross-links: application to oxopropenyl-deoxyadenosine. Chem Res Toxicol 27:136-46|
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