Cynthia J. Burrows
Distinguished Professor of Chemistry
B.A. University of Colorado, Boulder
Ph.D. Cornell University
Research
The heterocyclic bases of nucleic acids are rich targets for both toxins that damage DNA and drugs that interact with DNA and RNA. Our laboratory investigates several different aspects of nucleic acid chemistry with particular emphasis on oxidative damage to DNA bases. Tools used in our lab include synthesis of modified nucleic acids, organic reaction mechanisms, structural analysis by ESI-MS and NMR, gel electrophoresis, PCR and enzyme biochemistry related to DNA polymerases.
Chemistry and Biochemistry of Guanine Oxidation Many health problems ranging from cancer to aging stem from oxidative damage to DNA. Within DNA, guanine is the site most susceptible to oxidation. We are currently investigating the mechanistic pathways of one-electron oxidation of G to 8-oxoG and leading on to guanidinohydantoin and spirodihydantoin products. Both the misinsertion of bases opposite new lesions by polymerases and their repair by DNA repair enzymes (the latter in collaboration with Sheila David) are under investigation. In RNA, oxidation of Gs forms the basis of a structural probe of this residue.
DNA-Protein Cross-Links. DNA oxidation can also lead to the formation of covalent adducts to bases, and the lysine-rich motifs that bind DNA provide abundant nucleophiles for cross-linking. Studies current include the elucidation of the structures and mechanisms by which oxidation of either DNA or a protein can lead to cross-link formation as well as investigations of other cellular nucleophiles such as spermine. Adducts to DNA formed from oxidation of redox active phenols (tyrosine, catechols, estrogen, etc.) are also under investigation.
References
1. Xu X, Muller JG, Ye Y, Burrows CJ (2008) DNA-protein cross-links between guanine and lysine depend on the mechanism of oxidation for formation of C5 vs. C8 adducts. J. Am. Chem. Soc. 130:703-709
2. Munk BH, Burrows CJ, Schlegel HB (2008) An exploration of mechanisms for the transformation of 8-oxoguanine to guanidinohydantoin and spiroiminodihydantoin by density functional theory. J. Am. Chem. Soc. 130:5245-5256
3. Krishnamurthy N, Muller JG, Burrows CJ, David SS (2007) Unusual structural features of hydantoin lesions translate into efficient recognition by Escherichia coli Fpg. Biochemistry 46:9355-9365
4. Zhao X, Muller JG, Halasyam M, David SS, Burrows CJ (2007) In vitro DNA ligation of oligodeoxynucleotides containing oxidized purine lesions by bacteriophage T4 DNA ligase. Biochemistry 46:3734-3744
5. Ye Y, Muller JG, Burrows CJ (2006) Synthesis and characterization of the oxidized dGTP lesions spiroiminodihydantoin-2'-deoxynucleoside-5'-triphosphate and guanidinohydantoin-2' -deoxynucleoside-5'-triphosphate. J. Org. Chem. 71:2181-2184
6. Johansen MJ, Muller JG, Xu X, Burrows CJ (2005) Oxidatively induced DNA-protein cross-linking between single-stranded binding protein (SSB) and oligodeoxynucleotides containing 8-oxo-7,8-dihydro-2’-deoxyguanosine. Biochemistry 44:5660-5671
7. Kornyushyna O, Stemmler AJ, Graybosch DM, Bergenthal I, Burrows CJ (2005) Synthesis of a metallopeptide-PNA conjugate and its oxidative cross-linking to a DNA target. Bioconj. Chem. 17:178-183
8. Hosford ME, Muller JG, and Burrows CJ (2004) Spermine participates in oxidative damage of guanosine and 8-oxoguanosine leading to deoxyribosylurea formation. J. Am. Chem. Soc. 126:9540-9541
