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Carcinogenesis Advance Access originally published online on January 6, 2009
Carcinogenesis 2009 30(3):408-415; doi:10.1093/carcin/bgp004
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The DNA repair protein NBS1 influences the base excision repair pathway

Daniel Sagan1,2,*, Romy Müller1, Carina Kröger1, Arunee Hematulin1,2, Simone Mörtl1 and Friederike Eckardt-Schupp1

1 Institute of Radiation Biology, Helmholtz Centre Munich—German Research Centre for Environmental Health, Ingolstaedter Landstrasse 1, 85758 Neuherberg, Germany
2 Department of Radiological Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand

* To whom correspondence should be addressed. Tel: +66 55 26 10 00 ext. 62 79; Fax: +66 55 26 19 35; Email: daniel.sagan{at}helmholtz-muenchen.de

NBS1 fulfills important functions for the maintenance of genomic stability and cellular survival. Mutations in the NBS1 (Nijmegen Breakage Syndrome 1) gene are responsible for the Nijmegen breakage syndrome (NBS) in humans. The symptoms of this disease and the phenotypes of NBS1-defective cells, especially their enhanced radiosensitivity, can be explained by an impaired DNA double-strand break-induced signaling and a disturbed repair of these DNA lesions. We now provide evidence that NBS1 is also important for cellular survival after oxidative or alkylating stress where it is required for the proper initiation of base excision repair (BER). NBS1 downregulated cells show reduced activation of poly-(adenosine diphosphate-ribose)-polymerase-1 (PARP1) following genotoxic treatment with H2O2 or methyl methanesulfonate, indicating impaired processing of damaged bases by BER as PARP1 activity is stimulated by the single-strand breaks intermediately generated during this repair pathway. Furthermore, extracts of these cells have a decreased capacity for the in vitro repair of a double-stranded oligonucleotide containing either uracil or 8-oxo-7,8-dihydroguanine to trigger BER. Our data presented here highlight for the first time a functional role for NBS1 in DNA maintenance by the BER pathway.

Abbreviations: AP, apurinic or apyrimidic; BER, base excision repair; ds, double stranded; DSB, double-strand break; EDTA, ethylenediaminetetraacetic acid; MMS, methyl methanesulfonate; MRN, MRE11/RAD50/NBS1; NAD, nicotinamide adenine dinucleotide; NBS, Nijmegen breakage syndrome; PAR, poly-(adenosine diphosphate-ribose); PARP1, poly-(adenosine diphosphate-ribose)-polymerase-1; PBS, phosphate-buffered saline; POLβ, polymerase beta; 8-oxoG, 8-oxo-7,8-dihydroguanine; RNAi, RNA interference; RPE, retinal pigment epithelial; siRNA, short interfering RNA; SSB, single-strand break; WS, Werner syndrome

Received August 31, 2008; revised November 25, 2008; accepted December 22, 2008.


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