title: DNA tandem lesion repair by strand displacement synthesis and nucleotide excision repair.
abstract: DNA tandem lesions are comprised of two contiguously damaged nucleotides. This subset of clustered lesions is produced by a variety of oxidizing agents, including ionizing radiation. Clustered lesions can inhibit base excision repair (BER). We report the effects of tandem lesions composed of a thymine glycol and a 5'-adjacent 2-deoxyribonolactone (LTg) or tetrahydrofuran abasic site (FTg). Some BER enzymes that act on the respective isolated lesions do not accept the tandem lesion as a substrate. For instance, endonuclease III (Nth) does not excise thymine glycol (Tg) when it is part of either tandem lesion. Similarly, endonuclease IV (Nfo) does not incise L or F when they are in tandem with Tg. Long-patch BER overcomes inhibition by the tandem lesion. DNA polymerase beta (Pol beta) carries out strand displacement synthesis, following APE1 incision of the abasic site. Pol beta activity is enhanced by flap endonuclease (FEN1), which cleaves the resulting flap. The tandem lesion is also incised by the bacterial nucleotide excision repair system UvrABC with almost the same efficiency as an isolated Tg. These data reveal two solutions that DNA repair systems can use to counteract the formation of tandem lesions.
authors.affiliation: Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Imoto
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bransfield
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.forename: Marc M
authors.initials: MM
authors.lastname: Greenberg
mesh_terms: D004247:DNA / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics* / Q000528:radiation effects; D015394:Molecular Structure; D009711:Nucleotides / Q000737:chemistry* / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013936:Thymidine / Q000031:analogs & derivatives / Q000378:metabolism; D044366:Transition Temperature
chemical_list: D009711:Nucleotides; C029390:thymidine glycol; D004247:DNA; D019951:DNA Polymerase beta; D010727:Phosphoric Diester Hydrolases; D013936:Thymidine