Role of XRCC1 in the coordination and stimulation of oxidative DNA damage repair initiated by the DNA glycosylase hOGG1.
XRCC1 participates in DNA single strand break and base excision repair (BER) to preserve genetic stability in mammalian cells. XRCC1 participation in these pathways is mediated by its interactions with several of the acting enzymes. Here, we report that XRCC1 interacts physically and functionally with hOGG1, the human DNA glycosylase that initiates the repair by BER of the mutagenic oxidized base 8-oxoguanine. This interaction leads to a 2- to 3-fold stimulation of the DNA glycosylase activity of hOGG1. XRCC1 stimulates the formation of the hOGG1 Schiff-base DNA intermediate without interfering with the endonuclease activity of APE1, the second enzyme in the pathway. On the contrary, the stimulation in the appearance of the incision product seems to reflect the addition of the effects of XRCC1 on the two first enzymes of the pathway. The data presented support a model by which XRCC1 will pass on the DNA intermediate from hOGG1 to the endonuclease APE1. This results in an acceleration of the overall repair process of oxidized purines to yield an APE1-cleaved abasic site, which can be used as a substrate by DNA polymerase beta. More importantly, the results unveil a highly coordinated mechanism by which XRCC1, through its multiple protein-protein interactions, extends its orchestrating role from the base excision step to the resealing of the repaired DNA strand.
Marsin
Stéphanie
S
Département de Radiobiologie et Radiopathologie, UMR 217 CNRS, Commissariat à l'Energie Atomique, BP6, F-92265 Fontenay aux Roses, France.
Vidal
Antonio E
AE
Sossou
Marguerite
M
Ménissier-de Murcia
Josiane
J
Le Page
Florence
F
Boiteux
Serge
S
de Murcia
Gilbert
G
Radicella
J Pablo
JP
D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D005982:Glutathione Transferase / Q000235:genetics; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D011687:Purines / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D020798:Two-Hybrid System Techniques; D000076105:X-ray Repair Cross Complementing Protein 1
D004268:DNA-Binding Proteins; D011687:Purines; D011993:Recombinant Fusion Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D005982:Glutathione Transferase; D019951:DNA Polymerase beta; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase