Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1.
XRCC1 protein is required for the repair of DNA single-strand breaks and genetic stability, and is essential for viability in mammals. XRCC1 functions as a scaffold protein by interacting and modulating polypeptide components of the single-strand break repair machinery, including AP endonuclease-1, DNA ligase IIIalpha, poly (ADP-ribose) polymerase, DNA polymerase beta and human polynucleotide kinase. We show here that the E6 protein of human papillomavirus type 1, 8 and 16 directly binds XRCC1. When tested in CHO derived XRCC1 'knock out' EM9 cells, co-expression of human papillomavirus 16 E6 with human XRCC1 reduced the ability of the latter protein to correct the methyl methane sulfate sensitivity of XRCC1 mutant CHO cell line EM9. These data identify a novel link between small DNA tumour viruses and DNA repair pathways, and suggest a novel explanation for the development of genomic instability in tissue cells persistently infected with papillomaviruses.
Sektion Experimentelle Virologie, Universitätsklinikum Tuebingen, Elfriede-Aulhorn Strasse 6, D-72076 Tuebingen, Germany. tsiftner@med.uni-tuebingen.de
Thomas
T
Iftner
Michaela
M
Elbel
Betti
B
Schopp
Thomas
T
Hiller
Joanna I
JI
Loizou
Keith W
KW
Caldecott
Frank
F
Stubenrauch
D000818:Animals; D016466:CHO Cells; D002472:Cell Transformation, Viral / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004260:DNA Repair; D004277:DNA, Single-Stranded / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000378:metabolism* / Q000494:pharmacology*; D027383:Papillomaviridae / Q000472:pathogenicity; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000076105:X-ray Repair Cross Complementing Protein 1
D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C466081:E6 protein, Human papillomavirus type 8; C466080:E6 protein, human papillomavirus type 1; D009153:Mutagens; D009856:Oncogene Proteins, Viral; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D008741:Methyl Methanesulfonate