title: Repair of the major lesion resulting from C5'-oxidation of DNA.
abstract: Oxidation of the C5'-position of DNA results in direct strand scission. The 3'-fragments produced contain DNA lesions at their 5'-termini. The major DNA lesion contains an aldehyde at its C5'-position, but its nucleobase is unmodified. Excision of the lesion formed from oxidation of thymidine (T-al) is achieved by strand displacement synthesis by DNA polymerase β (Pol β) in the presence or absence of flap endonuclease 1 (FEN1). Pol β displaces T-al and thymidine with comparable efficiency, but less so than a chemically stabilized abasic site analogue (F). FEN1 cleaves the flaps produced during strand displacement synthesis that are two nucleotides or longer. A ternary complex containing T-al is also a substrate for the bacterial UvrABC nucleotide excision repair system. The sites of strand scission are identical in ternary complexes containing T-al, thymidine, or F. UvrABC incision efficiency of these ternary complexes is comparable as well but significantly slower than a duplex substrate containing a bulky substituted thymidine. However, cleavage occurs only on the 5'-fragment and does not remove the lesion. These data suggest that unlike many lesions the redundant nature of base excision and nucleotide excision repair systems does not provide a means for removing the major damage product produced by agents that oxidize the C5'-position. This may contribute to the high cytotoxicity of drugs that oxidize the C5'-position in DNA.
authors.affiliation: Department of Chemistry, Johns Hopkins University, 3400 N Charles St, Baltimore, Maryland 21218, United States.
authors.forename: Kwan-Young
authors.initials: KY
authors.lastname: Jung
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kodama
authors.forename: Marc M
authors.initials: MM
authors.lastname: Greenberg
mesh_terms: D001483:Base Sequence; D004249:DNA Damage / Q000187:drug effects; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004260:DNA Repair; D004492:Edetic Acid / Q000633:toxicity; D005290:Ferric Compounds / Q000633:toxicity; D005296:Ferrous Compounds / Q000633:toxicity; D005609:Free Radicals / Q000633:toxicity; D017665:Hydroxyl Radical / Q000633:toxicity; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction / Q000187:drug effects; D011685:Purine Nucleotides / Q000633:toxicity
chemical_list: D005290:Ferric Compounds; D005296:Ferrous Compounds; D005609:Free Radicals; D011685:Purine Nucleotides; C055526:Fe(II)-EDTA; D017665:Hydroxyl Radical; D004492:Edetic Acid; D019951:DNA Polymerase beta; C019179:Fe(III)-EDTA