title: Effects of (5'S)-5',8-cyclo-2'-deoxyadenosine on the base excision repair of oxidatively generated clustered DNA damage. A biochemical and theoretical study.
abstract: The presence of 5',8-cyclo-2'-deoxyadenosine (5'S)-cdA induces modifications in the geometry of the DNA duplex in the 5'-end direction of the strand and in the 3'-end direction of the complementary strand. As a consequence, the enzymes are probably not able to adjust their active sites in this rigid structure. Additionally, clustered DNA damage sites, a signature of ionising radiation, pose a severe challenge to a cell's repair machinery, particularly base excision repair (BER). To date, clusters containing a DNA base lesion, (5'S)-cdA, which is repaired by nucleotide excision repair, have not been explored. We have therefore investigated whether bistranded clusters containing (5'S)-cdA influence the repairability of an opposed AP site lesion, which is repaired by BER. Using synthetic oligonucleotides containing a bistranded cluster with (5'S)-cdA and an AP site at different interlesion separations, we have shown that in the presence of (5'S)-cdA on the 5'-end side, repair of the AP site by the BER machinery is retarded when the AP site is ≤8 bases from the (5'S)-cdA. However, if (5'S)-cdA is located on the 3'-end side with respect to the AP site, the effect on its repair is much weaker and totally disappears for distances ≥8 bases.
authors.affiliation: Food Science Department, Medical University of Lodz, Muszynskiego str. 1, 90-151 Lodz, Poland. Bolek.Karwowski@wp.pl.
authors.forename: Boleslaw T
authors.initials: BT
authors.lastname: Karwowski
authors.forename: Sophie
authors.initials: S
authors.lastname: Bellon
authors.forename: Peter
authors.initials: P
authors.lastname: O'Neill
authors.forename: Martine E
authors.initials: ME
authors.lastname: Lomax
authors.forename: Jean
authors.initials: J
authors.lastname: Cadet
mesh_terms: D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002467:Cell Nucleus / Q000737:chemistry; D003412:Cricetulus; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D004260:DNA Repair; D003839:Deoxyadenosines / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D010084:Oxidation-Reduction; D011789:Quantum Theory; D013816:Thermodynamics; D051981:Uracil-DNA Glycosidase / Q000737:chemistry*
chemical_list: D003839:Deoxyadenosines; D009841:Oligonucleotides; C056752:8,5'-cyclo-2'-deoxyadenosine; D004247:DNA; D051981:Uracil-DNA Glycosidase