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Molecular and Cellular Biology, September 2005, p. 7625-7636, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7625-7636.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cooperation of the Cockayne Syndrome Group B Protein and Poly(ADP-Ribose) Polymerase 1 in the Response to Oxidative Stress

Tina Thorslund,1 Cayetano von Kobbe,2,{dagger} Jeanine A. Harrigan,2 Fred E. Indig,2 Mette Christiansen,1 Tinna Stevnsner,1 and Vilhelm A. Bohr2*

Danish Center for Molecular Gerontology, Department of Molecular Biology, University of Aarhus, Aarhus, Denmark,1 Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland2

Received 19 November 2004/ Returned for modification 17 December 2004/ Accepted 27 May 2005

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.

* Corresponding author. Mailing address: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825. Phone: (410) 558-8162. Fax: (410) 558-8157. E-mail: vbohr{at}nih.gov.

{dagger} Present address: Spanish National Cancer Centre (CNIO), Molecular Pathology Program, Madrid, Spain.

Molecular and Cellular Biology, September 2005, p. 7625-7636, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7625-7636.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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