Klungland A, Höss M, Gunz D, Constantinou A, Clarkson S G, Doetsch P W, Bolton P H, Wood R D, Lindahl T
Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire, United Kingdom.
Mol Cell. 1999 Jan;3(1):33-42. 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 beta, 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.
DNA中的氧化嘧啶可通过一种独特的碱基切除修复途径去除，该途径由人类细胞中的DNA糖基化酶-AP裂解酶hNth1启动。我们已经用重组蛋白重建了这条单残基置换途径，这些重组蛋白包括AP核酸内切酶HAP1/APE、DNA聚合酶β和DNA连接酶III-XRCC1异二聚体。利用这些蛋白，核苷酸切除修复酶XPG作为hNth1高效发挥功能的辅助因子。XPG蛋白促进hNth1与受损DNA的结合。在核苷酸切除修复中无活性的XPG催化位点突变体中，hNth1活性的刺激作用得以保留。这些数据支持了XP-G患者中柯凯恩综合征的发生与内源性氧化性DNA损伤切除效率低下有关的模型。
