Interaction with OGG1 is required for efficient recruitment of XRCC1 to base excision repair and maintenance of genetic stability after exposure to oxidative stress.
XRCC1 is an essential protein required for the maintenance of genomic stability through its implication in DNA repair. The main function of XRCC1 is associated with its role in the single-strand break (SSB) and base excision repair (BER) pathways that share several enzymatic steps. We show here that the polymorphic XRCC1 variant R194W presents a defect in its interaction with the DNA glycosylase OGG1 after oxidative stress. While proficient for single-strand break repair (SSBR), this variant does not colocalize with OGG1, reflecting a defect in its involvement in BER. Consistent with a role of XRCC1 in the coordination of the BER pathway, induction of oxidative base damage in XRCC1-deficient cells complemented with the R194W variant results in increased genetic instability as revealed by the accumulation of micronuclei. These data identify a specific molecular role for the XRCC1-OGG1 interaction in BER and provide a model for the effects of the R194W variant identified in molecular cancer epidemiology studies.
CEA, Institute of Cellular and Molecular Radiobiology, Fontenay-aux-Roses, France INSERM, U967, Fontenay-aux-Roses, France Université Paris Diderot, U967, Fontenay-aux-Roses, France Université Paris Sud, U967, Fontenay-aux-Roses, France anna.campalans@cea.fr pablo.radicella@cea.fr.
Anna
A
Campalans
Institute of Pharmacy and Biochemistry, University of Mainz, Mainz, Germany.
Eva
E
Moritz
CEA, Institute of Cellular and Molecular Radiobiology, Fontenay-aux-Roses, France INSERM, U967, Fontenay-aux-Roses, France Université Paris Diderot, U967, Fontenay-aux-Roses, France Université Paris Sud, U967, Fontenay-aux-Roses, France.
Thierry
T
Kortulewski
CEA, DSV, iMETI, SEPIA, Fontenay-aux-Roses, France.
Denis
D
Biard
Institute of Pharmacy and Biochemistry, University of Mainz, Mainz, Germany.
Bernd
B
Epe
CEA, Institute of Cellular and Molecular Radiobiology, Fontenay-aux-Roses, France INSERM, U967, Fontenay-aux-Roses, France Université Paris Diderot, U967, Fontenay-aux-Roses, France Université Paris Sud, U967, Fontenay-aux-Roses, France anna.campalans@cea.fr pablo.radicella@cea.fr.
J Pablo
JP
Radicella
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D045647:DNA Glycosylases / Q000032:analysis / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps; D000076105:X-ray Repair Cross Complementing Protein 1
D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human