How DNA and RNA are Oxidatively Damaged
DNA damage by agents such as radiolysis and many antitumor antibiotics involves the formation of radical intermediates. Oxidative RNA damage is important in neurological diseases and in studies on RNA structure/folding. We use organic chemistry to independently synthesize putative reactive intermediates at defined sites in oligonucleotides to address questions concerning how nucleic acids are oxidatively damaged. The reactivity of these biologically important species is determined using a variety of tools that include isotopic labeling, electrospray and MALDI-TOF mass spectrometry, kinetics, enzymes, and molecular modeling.\
Using this approach we have resolved mechanistic controversies and discovered novel nucleic acid damage pathways. Most recently, we have applied this approach to studying DNA damage in nucleosome core particles by independently generating protein radicals in engineered histones.
For relevant publications see:
• Direct Strand Scission in Double Stranded RNA via a C5-Pyrimidine Radical. Resendiz, M. J. E.; Pottiboyina, V.; Sevilla, M. D.; Greenberg, M. M. J. Am. Chem. Soc. 2012, 134, 3917-3924.
• DNA Double Strand Cleavage via Interstrand Hydrogen Atom Transfer. Taverna Porro, M. L.; Greenberg, M. M. J. Am. Chem. Soc. 2013, 135, 16368-16371. “Spotlighted” in the J. Am. Chem. Soc. 2013, 135, 16745. Cited by Faculty1000: http://f1000.com/prime/718152314?bd=1&ui=21843. (PMC: 3852885)
•5.6-Dihydropyrimidine Peroxyl Radical Reactivity in DNA. San Pedro, J. M. N.; Greenberg, M. M. J. Am. Chem. Soc. 2014, 136, 3928-3936. (PMC: 3980663)
• DNA Damage by Histone Radicals in Nucleosome Core Particles. Zhou, C.; Greenberg, M. M. J. Am. Chem. Soc. 2014, 136, 6562-6565. (PMC: 4017609)
• Rapid RNA Strand Scission Following C2′-Hydrogen Atom Abstraction. Paul, R.; Greenberg, M. M. J. Am. Chem. Soc. 2015, 137, 596-599.