Cooperation of the Cockayne syndrome group B protein and poly(ADP-ribose) polymerase 1 in the response to oxidative stress.
Cockayne syndrome (CS) is a rare genetic disorder characterized as a segmental premature-aging syndrome. The CS group B (CSB) protein has previously been implicated in transcription-coupled repair, transcriptional elongation, and restoration of RNA synthesis after DNA damage. Recently, evidence for a role of CSB in base excision repair of oxidative DNA lesions has accumulated. In our search to understand the molecular function of CSB in this process, we identify a physical and functional interaction between CSB and poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a nuclear enzyme that protects the integrity of the genome by responding to oxidative DNA damage and facilitating DNA repair. PARP-1 binds to single-strand DNA breaks which activate the catalytic ability of PARP-1 to add polymers of ADP-ribose to various proteins. We find that CSB is present at sites of activated PARP-1 after oxidative stress, identify CSB as a new substrate of PARP-1, and demonstrate that poly(ADP-ribosyl)ation of CSB inhibits its DNA-dependent ATPase activity. Furthermore, we find that CSB-deficient cell lines are hypersensitive to inhibition of PARP. Our results implicate CSB in the PARP-1 poly(ADP-ribosyl)ation response after oxidative stress and thus suggest a novel role of CSB in the cellular response to oxidative damage.
Thorslund
Tina
T
Danish Center for Molecular Gerontology, Department of Molecular Biology, University of Aarhus.
von Kobbe
Cayetano
C
Harrigan
Jeanine A
JA
Indig
Fred E
FE
Christiansen
Mette
M
Stevnsner
Tinna
T
Bohr
Vilhelm A
VA
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003057:Cockayne Syndrome; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes; D006801:Humans; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D013379:Substrate Specificity
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000075223:Poly-ADP-Ribose Binding Proteins; D011065:Poly(ADP-ribose) Polymerases; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes