THE DNA-REPAIR ENDONUCLEASE XPG BINDS TO PROLIFERATING CELL NUCLEAR ANTIGEN (PCNA) AND SHARES SEQUENCE ELEMENTS WITH THE PCNA BINDING REGIONS OF FEN-1 AND CYCLIN-DEPENDENT KINASE INHIBITOR P21

Proliferating cell nuclear antigen (PCNA) is a DNA polymerase accessor y factor that is required for DNA replication during S phase of the ce ll cycle and for resynthesis during nucleotide excision repair of dama ged DNA, PCNA binds to flap endonuclease 1 (FEN-1), a structure-specif ic endonuclease involved in DNA replication. Here we report the direct physical interaction of PCNA with xeroderma pigmentosum (XP) G, a str ucture-specific repair endonuclease that is homologous to FEN-1, We ha ve identified a 28-amino acid region of human FEN-1 (residues 328-355) and a 29-amino acid region of human XPG (residues 981-1009) that cont ains the PCNA binding activity, These regions share key hydrophobic re sidues with the PCNA-binding domain of the cyclin-dependent kinase inh ibitor p21(Waf1/Cip1), and all three competed with one another for bin ding to PCNA. A conserved arginine in FEN-1 (Arg(339)) and XPG (Arg(99 2)) was found to be crucial for PCNA binding activity, R992A and R992E mutant forms of XPG failed to fully reconstitute nucleotide excision repair in an in vivo complementation assay, These results raise the po ssibility of a mechanistic linkage between excision and repair synthes is that is mediated by PCNA.