Base Excision Repair of Oxidative DNA Damage Activated by XPG Protein

• Published in: Molecular cell 1999, Vol.3 (1), p.33-42
• Main Authors: Klungland, Arne, Höss, Matthias, Gunz, Daniela, Constantinou, Angelos, Clarkson, Stuart G, Doetsch, Paul W, Bolton, Philip H, Wood, Richard D, Lindahl, Tomas
• Format: Article
• Language: English
• Subjects: Base Sequence; Binding Sites - genetics; Cockayne Syndrome - genetics; Deoxyribonuclease (Pyrimidine Dimer); DNA Damage - genetics; DNA Repair - genetics; DNA-Binding Proteins - genetics; Endodeoxyribonucleases; Endonucleases; Enzyme Activation - genetics; Escherichia coli Proteins; Humans; Molecular Sequence Data; Mutation - genetics; Nuclear Proteins; Oxidative Stress - genetics; Pyrimidines - metabolism; Recombinant Proteins - genetics; Transcription Factors; Uracil - analogs & derivatives; Uracil - metabolism
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/S1097-2765(00)80172-0

Oxidized pyrimidines in DNA are removed by a distinct base excision repair pathway initiated by the DNA glycosylase—AP lyase hNth1 in human cells. We have reconstituted this single-residue replacement pathway with recombinant proteins, including the AP endonuclease HAP1/APE, DNA polymerase β, and DNA ligase III-XRCC1 heterodimer. With these proteins, the nucleotide excision repair enzyme XPG serves as a cofactor for the efficient function of hNth1. XPG protein promotes binding of hNth1 to damaged DNA. The stimulation of hNth1 activity is retained in XPG catalytic site mutants inactive in nucleotide excision repair. The data support the model that development of Cockayne syndrome in XP-G patients is related to inefficient excision of endogenous oxidative DNA damage.