Action of multiple base excision repair enzymes on the 2'-deoxyribonolactone.
Free radical attack on the sugar-phosphate backbone generates oxidized apurinic/apyrimidinic (AP) residues in DNA. 2'-deoxyribonolactone (dL) is a C1'-oxidized AP site damage generated by UV and gamma-irradiation, and certain anticancer drugs. If not repaired dL produces G-->A transitions in Escherichia coli. In the base excision repair (BER) pathway, AP endonucleases are the major enzymes responsible for 5'-incision of the regular AP site (dR) and dL. DNA glycosylases with associated AP lyase activity can also efficiently cleave regular AP sites. Here, we report that dL is a substrate for AP endonucleases but not for DNA glycosylases/AP lyases. The kinetic parameters of the dL-incision were similar to those of the dR. DNA glycosylases such as E. coli formamidopyrimidine-DNA glycosylase, mismatch-specific uracil-DNA glycosylase, and human alkylpurine-DNA N-glycosylase bind strongly to dL without cleaving it. We show that dL cross-links with the human proteins 8-oxoguanine-DNA (hOGG1) and thymine glycol-DNA glycosylases (hNth1), and dR cross-links with Nth and hNth1. These results suggest that dL and dR induced genotoxicity might be strengthened by BER pathway in vivo.
Faure
Virginie
V
LEDSS-UMR 5616, ICMG-FR 2607, BP 53, Université Joseph Fourier, 38041 Grenoble Cedex 9, France.
Saparbaev
Murat
M
Dumy
Pascal
P
Constant
Jean-François
JF
D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000737:chemistry*; D004789:Enzyme Activation; D007783:Lactones / Q000737:chemistry*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D012263:Ribonucleosides / Q000737:chemistry*; D012266:Ribose / Q000031:analogs & derivatives* / Q000737:chemistry*; D013400:Sugar Acids / Q000737:chemistry*
D007783:Lactones; D009838:Oligodeoxyribonucleotides; D012263:Ribonucleosides; D013400:Sugar Acids; C057020:ribonolactone; D012266:Ribose; D045643:DNA Repair Enzymes