Structure of DNA polymerase beta with the mutagenic DNA lesion 8-oxodeoxyguanine reveals structural insights into its coding potential.
Oxidative damage to DNA generates 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). During DNA replication and repair synthesis, 8-oxodG can pair with cytosine or adenine. The ability to accurately replicate through this lesion depends on the DNA polymerase. We report the first structure of a polymerase with a promutagenic DNA lesion, 8-oxodG, in the confines of its active site. The modified guanine residue is in an anti conformation and forms Watson-Crick hydrogen bonds with an incoming dCTP. To accommodate the oxygen at C8, the 5'-phosphate backbone of the templating nucleotide flips 180 degrees. Thus, the flexibility of the template sugar-phosphate backbone near the polymerase active site is one parameter that influences the anti-syn equilibrium of 8-oxodG. Our results provide insights into the mechanisms employed by polymerases to select the complementary dNTP.
Krahn
Joseph M
JM
Laboratory of Structural Biology, National Institute of Environmental Health Sciences, NIH, P.O. Box 12233, Research Triangle Park, NC 27709, USA.
Beard
William A
WA
Miller
Holly
H
Grollman
Arthur P
AP
Wilson
Samuel H
SH
D001665:Binding Sites; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000737:chemistry* / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D017434:Protein Structure, Tertiary
D003838:Deoxyadenine Nucleotides; C024829:8-hydroxyguanine; D006147:Guanine; D019951:DNA Polymerase beta; C026600:2'-deoxyadenosine triphosphate