Deficiency of the Cockayne syndrome B (CSB) gene aggravates the genomic instability caused by endogenous oxidative DNA base damage in mice

Trapp, Christian; Reite, Karen; Klungland, Arne; Epe, Bernd

doi:10.1038/sj.onc.1210167

Cited by 40 publications

(22 citation statements)

References 31 publications

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“…Mice lacking the gene for this protein, however, demonstrate slow repair of the lesion, suggesting that an alternate repair pathway exists (19). The identity of this pathway has been the subject of some controversy, although TCR has been implicated given that mice lacking the gene for the TCR Cockayne syndrome B (Csb) protein in an Ogg1 knockout background accumulate more genomic mutations and oxidative damage with age than mice lacking Ogg1 alone (21,22). With the mammalian TM system reported here the respective contributions of Ogg1-mediated BER vs. Csb-mediated TCR in the repair of 8OG lesions can be directly compared in congenic mouse embryonic fibroblasts (MEFs).…”

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confidence: 99%

8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells

Saxowsky¹,

Meadows²,

Klungland

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

117

136

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DNA repair ͉ MAP kinase ͉ Csb ͉ transcription-coupled repair ͉ tumorigenesis C ells use numerous mechanisms to neutralize various reactive species before they can damage DNA, as well as overlapping pathways to repair the damage, thus protecting genomic integrity. DNA damage can result in a number of potential outcomes for a mammalian cell (1), including permanent fixation of the damage during replication, leading to a heritable mutation. Replication-centric models of mutagenesis have provided valuable information regarding routes of mutagenesis under conditions of continuous cell growth and replication. These models, however, largely ignore transcription, the other major nucleic acid transaction essential to the cell. In slowly growing or nondividing cells, in which DNA replication is greatly diminished or altogether absent (e.g., terminally differentiated mammalian cells [2]), transcription must continue to provide the cell with the proteins necessary for normal physiologic processes. As such, the interaction of DNA damage with the transcription machinery occurs more frequently than with the replication apparatus.Many types of DNA damage are repaired with greater efficiency if they occur in the template strand of a transcribed gene rather than the nontemplate strand or a nontranscribed region of the genome (3, 4). Bulky lesions that distort the DNA helix will arrest RNA polymerase (RNAP) at the site of damage, promoting transcription-coupled repair (TCR) and allowing the generation of full-length, normal transcripts (5, 6). However, frequently occurring nonbulky lesions, such as 8-oxoguanine

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confidence: 99%

8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells

Saxowsky¹,

Meadows²,

Klungland

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

117

136

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“…Ϫ/Ϫ mice accumulate several-fold higher levels of modified purines than csb Ϫ/Ϫ mice (21) and have elevated levels of G 3 T transversion mutations (22). CSB also interacts with other BER enzymes, including AP endonuclease 1 (23) and poly(ADP-ribose) polymerase (PARP1) (24).…”

mentioning

confidence: 99%

Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase

Müftüoğlu

Souza-Pinto

Doğan

et al. 2009

Journal of Biological Chemistry

100

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Cockayne syndrome (CS) 6 is a segmental premature aging syndrome with progressive neurological degeneration (1). CS is caused by mutations in CS complementation groups A (CSA) or B (CSB) genes (2, 3). Approximately 80% of CS patients have mutations in the CSB gene, which encodes a 168-kDa protein belonging to the SWI/SNF2 family of chromatin remodeling proteins (4). Cells from CS patients are hypersensitive to UV radiation-induced DNA damage, and the CSB protein is required for the transcription-coupled nucleotide excision repair of UV radiation-induced DNA lesions (cyclobutane pyrimidine dimers and 6-pyrimidine-4-pyrimidone products) (5). CSB is also believed to play a role in transcription elongation and interacts with the RNA polymerase II elongation complex (6). The molecular basis of the progressive neurological defects in CS patients, however, remains unknown; it has been proposed that neurological symptoms in CS may be due to defective repair and/or processing of oxidative DNA damage in CSB-deficient cells (7).Oxidative DNA damage can be caused by endogenous and exogenous agents. Reactive oxygen species, including highly reactive hydroxyl radicals, are formed as byproducts of normal metabolism, mostly during the process of mitochondrial respiration. It has been estimated that up to 2% of all the O 2 consumed by respiration may be released as reactive oxygen species (8, 9). The central nervous system relies exclusively on mitochondria to generate ATP through oxidative metabolism. As a result, neurons are susceptible to increased levels of oxidative stress, and elevated levels of reactive oxygen species have been implicated in the etiology of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington diseases and amyotrophic lateral sclerosis (for a review, see Ref. 10).Hydroxyl radicals attack DNA bases and the sugar-phosphate DNA backbone, generating modified bases and singlestranded DNA (ssDNA) breaks, respectively (11). Many oxida-

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“…Csb m/m /Ogg1 À/À mice were bred from Ogg1 À/À mice (4) and Csb m/m mice (7) as described previously (9). The generation of Csb m/m / Ogg1 À/À mice carrying the bacterial lacI gene (BigBlue mice) and of repairproficient comparisons, which were used for mutation analyses, has also been described (8 …”

Section: Methodsmentioning

confidence: 99%

“…These result in elevated spontaneous mutation frequencies, mostly G:C to T:A transversions characteristic for 8-oxoG (4,5). The accumulation of the oxidative purine modifications and of the resulting mutations are even more pronounced in Csb m/m /Ogg1 À/À mice, 3 which additionally lack a back-up repair mechanism for this type of damage mediated by Cockayne syndrome B protein (8,9). The CSB deficiency alone has no significant effect on the basal levels of oxidative base modifications and on the spontaneous mutation rates (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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The Peroxisome Proliferator WY-14,643 Promotes Hepatocarcinogenesis Caused by Endogenously Generated Oxidative DNA Base Modifications in Repair-Deficient Csbm/m/Ogg1−/− Mice

Trapp

Schwarz²,

Epe³

2007

Cancer Research

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Basal levels of endogenously generated oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) mice, which were f3-fold higher than in the repair-proficient mice, declined by 39% under the treatment, whereas the frequencies in the livers of the repair-proficient animals remained unchanged. Preneoplastic lesions (staining positive or negative for glucose-6-phoshatase) developed in the livers of both wild-type and Csb m/m /Ogg1 À/À mice after 30 weeks.Both the numbers and the total volumes of the lesions were f6-fold higher in the repair-deficient mice than in the wildtype mice. The results indicate that spontaneous mutations generated from endogenous oxidative DNA base damage efficiently translate into increased tumorigenesis when cell proliferation is stimulated. [Cancer Res 2007;67(11):5156-61]

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Deficiency of the Cockayne syndrome B (CSB) gene aggravates the genomic instability caused by endogenous oxidative DNA base damage in mice

Cited by 40 publications

References 31 publications

8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells

8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells

Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase

The Peroxisome Proliferator WY-14,643 Promotes Hepatocarcinogenesis Caused by Endogenously Generated Oxidative DNA Base Modifications in Repair-Deficient Csbm/m/Ogg1−/− Mice

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