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"Synthesis of 2'-Fluorinated Nucleotides as Probes of DNA Repair Glycosylases"

Mr. Patrick Rogers, UC-Davis
(former undergraduate at HU, now pursuing Ph.D. at UC-Davis)

(with six co-authors, from UC-Davis, University of Utah, and University of Vermont)

DNA contains the necessary information for the function of living organisms. Under inflammatory conditions, reactive oxygen/nitrogen species (RONS) are a common byproduct secreted by macrophages. RONS have the potential to oxidize guanine (G) to a variety of oxidized lesions including 8-oxo-7,8-dihydroguanine (OG), guanidinohydantoin (Gh), and spiroiminodihydantoin (Sp). Although OG is present to a greater extent than the hydantoin lesions, both Gh and Sp are more mutagenic than OG and result in either G to T or G to C transversion mutations. In an attempt to combat the mutagenic potential of these hydantoin lesions in DNA, nature has developed DNA repair enzymes such as E. coli Fpg and Nei and its human homolog NEIL-1 to recognize and remove these hydantoin lesions in a variety of sequence contexts. Oligonucleotides containing Gh or Sp with a fluorine substituent at the C-2 prime position of the sugar were designed to make these hydantoin lesions more resistant to the enzyme catalyzed N-glycosidic bond cleavage by destabilizing the transition state. Multi-step chemical synthesis of the 2'-F-OG phosphoramidite in both the ribo and arabino configurations followed by solid phase DNA synthesis, and site-specific oxidation afforded oligonucleotides containing either 2'-F-Gh, and 2'-F-Sp in both the ribo and arabino configurations. These oligos were used to investigate the steps involved in the recognition and catalysis of the hydantoin lesions by DNA repair enzymes. Additionally, these oligos were used for co-crystal studies with NEIL-1 as well as its mimiviral ortholog, MvNei. Using these synthetically modified oligonucleotides, we aim to reveal key insights into the structure and function of these DNA repair glycosylases which cannot be obtained with the native substrates.

Location: Chemistry Building, Room G-08
Sep 2012
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