FASEB J. Uncover Your Biological Pathway
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by TUO, J.
Right arrow Articles by DIZDAROGLU, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by TUO, J.
Right arrow Articles by DIZDAROGLU, M.
(The FASEB Journal. 2003;17:668-674.)
© 2003 FASEB

Primary fibroblasts of Cockayne syndrome patients are defective in cellular repair of 8-hydroxyguanine and 8-hydroxyadenine resulting from oxidative stress

JINGSHENG TUO1, PAWEL JARUGA*, HENRY RODRIGUEZ*, VILHELM A. BOHR2 and MIRAL DIZDAROGLU*,2

Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA; and
* Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland, USA

2Correspondence: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224, USA. E-mail: vbohr{at}nih.gov; Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA. E-mail: miral{at}nist.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cockayne syndrome (CS) is a genetic human disease with clinical symptoms that include neurodegeneration and premature aging. The disease is caused by the disruption of CSA, CSB, or some types of xeroderma pigmentosum genes. It is known that the CSB protein coded by the CS group B gene plays a role in the repair of 8-hydroxyguanine (8-OH-Gua) in transcription-coupled and non-strand discriminating modes. Recently we reported a defect of CSB mutant cells in the repair of another oxidatively modified lesion 8-hydroxyadenine (8-OH-Ade). We show here that primary fibroblasts from CS patients lack the ability to efficiently repair these particular types of oxidatively induced DNA damages. Primary fibroblasts of 11 CS patients and 6 control individuals were exposed to 2 Gy of ionizing radiation to induce oxidative DNA damage and allowed to repair the damage. DNA from cells was analyzed using liquid chromatography/isotope dilution mass spectrometry to measure the biologically important lesions 8-OH-Gua and 8-OH-Ade. After irradiation, no significant change in background levels of 8-OH-Gua and 8-OH-Ade was observed in control human cells, indicating their complete cellular repair. In contrast, cells from CS patients accumulated significant amounts of these lesions, providing evidence for a lack of DNA repair. This was supported by the observation that incision of 8-OH-Gua- or 8-OH-Ade-containing oligodeoxynucleotides by whole cell extracts of fibroblasts from CS patients was deficient compared to control individuals. This study suggests that the cells from CS patients accumulate oxidatively induced specific DNA base lesions, especially after oxidative stress. A deficiency in cellular repair of oxidative DNA damage might contribute to developmental defects in CS patients.—Tuo, J., Jaruga, P., Rodriguez, H., Bohr, V. A., Dizdaroglu, M. Primary fibroblasts of Cockayne syndrome patients are defective in the cellular repair of 8-hydroxyguanine and 8-hydroxyadenine resulting from oxidative stress.


Key Words: CS • fibroblast cell line • gamma irradiation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cockayne syndrome (CS) is a multisystem, autosomal, recessive human disorder (1 2 3) . Its hallmarks include profound postnatal growth failure of the soma and brain, associated with premature senescence and progressive multiorgan degeneration (4 , 5) . There are three different genetic forms of CS. CS-A, a less severe form with survival into adolescence or young adult life, is linked to mutations of the CSA gene on chromosome 5. CS-B, a more prevalent and severe infantile form with a high rate of early death, is linked to mutations of the CSB gene on chromosome 10q11 and accounts for 80% of CS cases (4) . CS complexes with some types of xeroderma pigmentosum (XP) groups, defined as XP/CS complex, which is characterized by severe developmental and neurological dysfunctions and photosensitivity (6) . The XP/CS complex can result from mutations in any one of four XP genes (XPB, XPC, XPD,and XPG) (7) . The human CSB gene encodes a protein (CSB) with a molecular mass of 168 kDa and 1493 amino acids (2) . CSB is thought to be involved in cellular functions such as DNA repair and transcription regulation (8) . Hypersensitivity of fibroblasts from CS-B to killing by ultraviolet (UV) radiation indicates a defect in nucleotide excision repair (NER) of the cells (6 , 9 , 10) . One of the defective pathways in CS-B is transcription-coupled repair (TCR) of bulky adducts from UV radiation exposure (11 , 12) . Recent studies showed that DNA lesions such as 8-hydroxyguanine (8-OH-Gua) and thymine glycol that result from oxidative damage to DNA could be repaired by TCR with the involvement of XPG and CSB proteins (4 , 13 14 15) . We previously reported that whole cell extracts (WCEs) from primary CS cells incised 8-OH-Gua at a reduced level and that this defect in base excision repair (BER) is associated with down-regulated transcription of the human hOgg1 gene that encodes the DNA repair enzyme 8-OH-Gua glycosylase/apurinic lyase (hOgg1) (16) . This BER deficiency can be complemented by transfection of the cells with wild-type CSB (16) . Recently, we further showed that CS mutant cells are sensitive to {gamma} radiation and that this is associated with a defect of the cells in the repair of oxidative DNA damage in the general genome, distinct from its role in TCR (17) . Thus, those results indicated overlapping functions of CSB in BER and NER pathways, particularly with regard to repair of oxidative DNA damage. This in vitro observation of a BER defect was supported by the finding that 8-OH-Gua accumulated more in CSB null and motif VI mutant cells than in wild-type cells after exposure to oxidative stress by a low dose of {gamma} radiation (17) . Subsequently, this phenomenon was found to also be true for another oxidatively induced major DNA lesion 8-hydroxyadenine (8-OH-Ade) (18) . These studies were based on genetically engineered cell lines originally derived from CS1AN.S3.G2, a SV40-transformed human CS-B fibroblast cell line (3) . To further investigate the pathophysiological relevance of these results we have now used primary cell lines from CS patients to assay whether these individuals lack the ability to repair oxidative DNA damage and to more directly investigate whether this inability plays a role in the pathogenesis of CS.

The present study used 11 primary CS cell lines to test the capabilities of the cells in the removal of endogenously generated 8-OH-Gua and 8-OH-Ade in DNA under normal culture conditions and after exposure to low doses of {gamma} radiation. We found a slight increase in the accumulation of both compounds under basal conditions and a significant increase in the frequency of these lesions after the exposure to {gamma} radiation. The results may indicate that a defect in the removal of oxidative DNA damage contributes to the phenotypes of CS.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All reagents were purchased from Sigma (St. Louis, MO, USA) unless otherwise indicated. All cell culture media and supplements were obtained from Gibco BRL (Life Technologies, Grand Island, NY, USA).

Cells and culture conditions
Human fibroblast cell lines were obtained from Coriell Cell Repositories (Camden, NJ, USA; http://locus.umdnj.edu). The available details are listed in Table 1 . All CS cells were from patients with typical clinical features. Some cell lines lacked details in their complementation group classification and therefore were marked with a "?" in Table 1 . The control cells from apparently normal donors were matched specifically by Coriell cell repositories to corresponding CS cells in age, gender, and race. Since the cells arrived at various passages, the low passage cell lines were split and grown so as to match the higher passage ones. The experiments were carried out at 13th passage for all the cell lines, with at least one passage under our cell culture conditions. Three independent batches of each cell line were cultured. Cells were grown to confluence in minimum essential medium (MEM) containing 15% FBS, 2x MEM nonessential amino acids, 2x MEM vitamins, and 1x MEM essential amino acids.


View this table:
[in this window]
[in a new window]
  		Table 1. CSB cell lines and control cellsa

Exposure of cells to ionizing radiation, DNA isolation, and hydrolysis
Three independently cultured batches of each cell line, equilibrated in air, were used for each data point. Cells were exposed to {gamma} radiation at a dose of 2 Gy using a Gammacell 40 Exactor 137Cs {gamma} source (dose rate, 1.4 Gy/min). Genomic DNA was isolated from irradiated and control cells using a salting out procedure (17) . Cell pellets were resuspended in lysis buffer (0.5 M Tris-HCl at pH 8.0, 20 mM EDTA, 10 mM NaCl, 1% SDS, and 0.5 mg/mL proteinase K) and incubated at 37°C for 18 h. One-fourth volume of saturated NaCl was added and the samples were heated at 55°C for 10 min. After centrifugation for 30 min at 500 g, the DNA in the supernatant was precipitated with ethanol and resuspended in water after washing in 70% ethanol. The DNA samples were measured by UV spectroscopy. The UV spectra were monitored between the wavelengths of 200 and 350 nm to assure the quality of DNA and accurate quantification of DNA concentration. Aliquots of 70 µg of DNA samples were hydrolyzed to nucleosides as described (17) .

Liquid chromatography/isotope dilution-mass spectrometry
Measurement of 8-OH-Gua and 8-OH-Ade as their nucleoside forms 8-hydroxy-2'-deoxyguanosine (8-OH-dGuo) and 8-hydroxy-2'-deoxyadenosine (8-OH-dAdo), respectively, in enzymic hydrolysates of DNA samples was performed by liquid chromatography/isotope dilution mass spectrometry (LC/IDMS) using the stable isotope-labeled analogs of 8-OH-dGuo and 8-OH-dAdo as internal standards as previously described (17 18 19) .

In vitro incision of oligodeoxynucleotides containing 8-OH-Gua or 8-OH-Ade
WCEs were prepared as described (17) . A 29-mer oligodeoxynucleotide containing a single 8-OH-Gua at the position 11 and a 28-mer oligodeoxynucleotide containing a single 8-OH-Ade at position 11 were used as substrates for the incision assay (Table 2 ). The oligodeoxynucleotides were 5'-end labeled with 32P and annealed with the complementary strand as previously described (20) . Oligodeoxynucleotides with the same sequence but a normal GC pair at the position 11 were used as controls (Table 2) . The incision reaction contained 0.15 nmol of oligodeoxynucleotide duplex, 1 µg poly-[D(I-C-d(I-C)], 20 mM HEPES-KOH at pH 7.8, 100 mM KCl, 5 mM DTT, 5 mM EDTA, 2 mM MgCl2, and 40 µg protein of WCEs. Purified Escherichia coli formamidopyrimidine glycosylase (Fpg) was used as the positive control of the incision of 8-OH-Gua (17) . After incubation at 37°C for 3 h, the reaction was terminated by the addition of 0.8 µL of 10% SDS and 0.8 µL of 5 mg/mL proteinase K and incubated for 10 min at 55°C. In a 20 µL reaction mixture, DNA was precipitated by adding 2 µL of 5 mg/mL glycogen (Ambion), 4 µL of 11 M ammonium acetate, and 70 µL cold ethanol overnight at -20°C. Samples were centrifuged for 1 h at 4°C, followed by washing with 200 µL of 70% ethanol. After centrifugation at 12,000 g for 10 min, the pellet was dried in a SpeedVac and resuspended in 10 µL of formamide loading dye (5% EDTA, 0.02% bromophenol blue and 0.02% xylene cyanol in 95% formamide). Samples were then separated by 20% denaturing polyacrylamide gel electrophoresis (containing 7 M urea, 89 mM Tris-borate at pH 8.0 and 2 mM EDTA). The reaction products (11-mer oligodeoxynucleotides) were visualized by autoradiography and quantified on a PhosphorImager (Molecular Dynamics, Sunnyvale, CA, USA). The extent of the incision was calculated by comparing the band intensities of substrates and products.


View this table:
[in this window]
[in a new window]
  		Table 2. The oligodeoxynucleotides used in incision assaysa

Statistics
Groups were compared by means of one-way ANOVA tests. Duncan’s multiple range test was used for post hoc comparison of means. Differences were considered significant when P< 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In the present study, we assayed 11 primary cell lines from CS patients to test the ability of the cells to repair two major products of oxidative DNA damage: 8-OH-Gua and 8-OH-Ade (21) . Experiments were performed under normal culture conditions after exposure of patient cells to a low dose of {gamma} radiation to generate oxidative stress. Primary cell lines from six normal individuals were used as controls. Table 1 shows some characteristics of the cell lines used in this study. Three independent cultures of each cell line were assayed. Cells were exposed to 2 Gy of {gamma} radiation, then incubated for 30 min to allow for cellular repair. DNA was independently isolated from each culture before and after exposure to ionizing radiation. DNA samples were hydrolyzed to nucleosides with endo- and exonucleases. 8-OH-Gua and 8-OH-Ade were identified and quantified in DNA samples as their nucleoside forms 8-OH-dGuo and 8-OH-dAdo, respectively, using LC/IDMS as described previously (17 18 19) . The levels of 8-OH-dGuo and 8-OH-dAdo in genomic DNA from three independent samples are listed in Table 3 . Each value represents the mean ± SD from the measurement of three DNA samples isolated from three independently cultured batches of the same cell line. There were no statistically significant differences between the levels of 8-OH-dGuo or 8-OH-dAdo in CS and control cells before exposure of cells to {gamma} radiation. After exposure of cells to 2 Gy of {gamma} radiation followed by 30 min of incubation for cellular repair, the levels of 8-OH-dGuo or 8-OH-dAdo in CS cells were statistically greater than the levels in control cells, as shown in Table 3 , demonstrating an accumulation of these lesions in irradiated CS cells. The combined mean values ± SDs obtained using DNA samples from all 33 samples of CS cells and 18 samples of control cells are shown Fig. 1 a, b. These graphs show that there is no statistical difference between the levels of 8-OH-dGuo or 8-OH-dAdo in unirradiated control and CS cells. On the other hand, these graphs also show that the combined mean values of the levels of these compounds in exposed CS cells were statistically greater than those in irradiated control cells. Figure 1c shows the correlation of 8-OH-dGuo and 8-OH-dAdo levels in all cell lines used in this study (r=0.89, P<0.01). The accumulation of the two lesions in irradiated CS cells is clearly seen in this illustration, and there is a good correlation between the accumulations of these two compounds. Among the CS cells, two cell lines, GM01098 and GM02838, had greater levels of accumulation of both 8-OH-dGuo and 8-OH-dAdo than the other cell lines (Table 3) . GM01098 and GM02838 cells were from 20- and 24-year-old individuals, whereas the remaining age range varied from 1 to 11 years (Table 1) . In the control group, no age-related differences between the levels of 8-OH-dGuo or 8-OH-dAdo were observed, although the age range was similar to that of CS patients. These results may indicate an age-related decline in DNA repair in CS patients.


View this table:
[in this window]
[in a new window]
  		Table 3. The levels (lesions/106 nucleosides) of 8-OH-dGuo and 8-OH-dAdo in the genomic DNA at background and after exposure of the cells to {gamma} radiationa



View larger version (30K):
[in this window]
[in a new window]
  		Figure 1. Levels of 8-OH-dGuo and 8-OH-dAde in genomic DNA measured by LC/IDMS. *P< 0.05. a) The combined mean (± SD) values from Table 2 of the levels of 8-OH-dGuo from CS and control cells with or without exposure to {gamma} radiation. b) Combined mean (± SD) values from Table 2 of the levels of 8-OH-dAdo from CS and control cells with or without exposure to {gamma} radiation. c) Mean values from Table 2 of the levels of 8-OH-dGuo and 8-OH-dAdo in all samples measured in this study for correlation analysis. r = 0.89, P< 0.01.

We also obtained WCEs from cells of normal individuals and CS patients to perform the incision assays. Oligodeoxynucleotides containing a single 8-OH-Gua or 8-OH-Ade were treated with WCEs, then analyzed by polyacrylamide gel electrophoresis. Table 2 shows the sequence of oligodeoxynucleotides used in this incision assay. Figure 2 a, b illustrates the gels of damaged base incision assay. Two independent experiments with each WCE were performed. As expected, Fpg used as a control almost completely incised the oligodeoxynucleotide containing 8-OH-Gua (22) . It should be emphasized that Fpg exhibits only a weak activity for 8-OH-Ade (22) . The activities to incise 8-OH-Gua- and 8-OH-Ade-containing oligodeoxynucleotides in WCEs of CS cells were ~ 30% of those of WCEs of control cells. These results clearly show the decreased DNA repair activity of CS patient cells and are consistent with those results described above on the greater accumulation of 8-OH-Gua and 8-OH-Ade in CS patient cells than in cells of control individuals.



View larger version (82K):
[in this window]
[in a new window]
  		Figure 2. The denaturing polyacrylamine gels of the incision of 8-OH-Gua- and 8-OH-Ade-containing duplex oligodeoxynucleotides by WCEs. Control reactions were those using duplex oligodeoxynucleotides without any lesion as the substrate incubated with WCA of GM00969 cells (40 µg protein). Duplicate reactions were performed. Fpg indicates the reaction using 8-OH-Gua-containing oligodeoxynucleotide as the substrate incised by Fpg. a) The incision of 8-OH-Gua-containing duplex oligodeoxynucleotides by WCEs from control and CS cells. b) The incision of 8-OH-Ade-containing duplex oligodeoxynucleotides by WCEs from control and CS cells.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, 11 CS strains were assigned to at least two complementation groups: CS-B and the XP-C/CS complex. All cell lines were from patients with clinical features of CS. We found a deficiency of these cell lines in cellular repair of two major DNA lesions in genomic DNA after oxidative stress by ionizing radiation.

Oxidative DNA damage occurs in cells as a consequence of normal aerobic metabolism and by generation of oxygen-derived free radicals from exposure to ionizing radiation and other DNA-damaging agents (21) . This type of DNA damage appears to be one of the main causes of aging (23) . Oxygen-derived free radicals (most notably the hydroxyl radical) react with DNA, generating a variety of structural modifications including base and sugar lesions, strand breaks, 8,5'-cyclopurine 2'-deoxyribonucleosides, and DNA–protein cross-links (21) . Many of the base lesions possess lethal or mutagenic properties (24) . DNA lesions can be repaired in cells by various repair mechanisms (25) . Generally, damaged base residues in DNA can be removed by one of two separate excision repair processes (26 , 27) . The defect in cellular repair of oxidative DNA damage in cells of CS patients may result from an incompetence in BER and reduced expression of BER factor(s) (13 14 15 16 17) . 8-OH-Gua and 8-OH-Ade, which were identified in the present study, are among the well-known major products of hydroxyl radical attack on guanine and adenine, respectively, in DNA in vitro and in vivo (21) . The biological effects of 8-OH-Gua were extensively investigated in the past and were found to be strongly mutagenic leading to G->T transversions (28 29 30) . Human Ogg1 is the only enzyme in humans so far discovered for the removal of 8-OH-Gua from DNA in BER (31) . We have observed a functional cross-talk between CSB and hOgg1 proteins (32) . The evidence suggests that CSB exists in the complex of BER of 8-OH-Gua and facilitates the expression of hOgg1 (16 , 32) . Reduced removal of oxidative pyrimidine damage from transcribed DNA strands was observed in cells from CS groups A and B (33) . A deficiency in the removal of 8-OH-Gua by XPA cells was also reported (34) . The other primary substrate of hOgg1 is 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) (31) , which is formed by hydroxyl radical attack on guanine, followed by one-electron reduction (21) . By analogy to 8-OH-Gua, the repair of FapyGua in CS cells might also be defective. However, this compound was not identified in the present work due to the lack of an LC/IDMS methodology for its measurement.

Although to a lesser extent than 8-OH-Gua, 8-OH-Ade also possesses premutagenic properties inducing A->G and A->C mutations in mammalian cells (35 36 37 38 39 40) . In contrast to the repair of 8-OH-Gua, no specific enzyme has been reported for the repair of 8-OH-Ade, although this lesion is repaired in mammalian cells (18;41). Nevertheless, the fact that the accumulation of both 8-OH-Gua and 8-OH-Ade was observed in CS cells points to the involvement of CSB protein in repair mechanisms of these compounds. Our recent data indicated a reduced BER of 8-OH-Ade and its increased accumulation in genomic DNA in immortalized CSB cells (18) . The amount of 8-OH-dGuo correlated with those of 8-OH-dAdo in this study.

Accumulated DNA lesions from oxidative stress may be a cause of progeroid syndromes (42 43 44) . Recent clinical pathological evidence further indicates that oxidative stress contributes to CS development since large deposits of various oxidative induced products, including nitrotyrosine, advanced glycation end products, and 4-hydroxy-2-nonenal-modified protein, were detected in the globus pallidus of CS patients (45) . The deposition of nitrotyrosine especially implies the involvement of reactive nitrogen species in the pathogenesis of CS (45) . The reactive nitrogen species could also nitrate DNA base and result in possible genome instability (46) . It is likely that the accumulation of the products of oxidative DNA damage in CS patients as shown in the present study might also contribute to the pathogenesis of CS.

We could not map the contribution of CS-related genes to the repair of oxidative DNA damage in this study because of the lack of detailed genotypic information in the CS cell lines tested. Previous data indicate the importance of the motif VI of the putative helicase domain of CSB in BER of 8-OH-Gua and 8-OH-Ade (17;18). Although 5 of the 11 cell strains have been identified as CS complementation group B and 80% of CS individuals belong to CS-B, there are undoubtedly diverse genotypes among the cell lines either with regard to their complementation group or the specific mutation within the gene (1 , 47) . In spite of the possible diversity of the genotypes, all cell lines from CS patients show a higher accumulation of the oxidative DNA lesions after oxidative stress than its controls, suggesting that domains other than the motif VI in the gene might also play some role in the repair.

In conclusion, we show lower activity of DNA repair and the accumulation of two major oxidative stress-induced DNA lesions in primary fibroblasts of CS patients, demonstrating reduced capability of CS patients in the cellular repair of oxidative DNA damage. This study suggests that the failure to repair these two lesions or any other lesions resulting from oxidative DNA damage might contribute to the pathogenesis of CS.


   FOOTNOTES
 
1 Current address: Laboratory of Immunology, National Eye Institute, National Institute of Health, Bethesda, MD 20892, USA

Received for publication August 28, 2002. Accepted for publication December 19, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Cleaver, J. E., Thompson, L. H., Richardson, A. S., States, J. C. (1999) A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum. Mutat. 14,9-22[CrossRef][Medline]
  2. Troelstra, C., Odijk, H., de Wit, J., Westerveld, A., Thompson, L. H., Bootsma, D., Hoeijmakers, J. H. (1990) Molecular cloning of the human DNA excision repair gene ERCC-6. Mol. Cell. Biol. 10,5806-5813[Abstract/Free Full Text]
  3. Troelstra, C., van Gool, A., de Wit, J., Vermeulen, W., Bootsma, D., Hoeijmakers, J. H. (1992) ERCC6, a member of a subfamily of putative helicases, is involved in Cockayne's syndrome and preferential repair of active genes. Cell 71,939-953[CrossRef][Medline]
  4. Nance, M. A., Berry, S. A. (1992) Cockayne syndrome: review of 140 cases. Am. J. Med. Genet. 42,68-84[CrossRef][Medline]
  5. Soffer, D., Grotsky, H. W., Rapin, I., Suzuki, K. (1979) Cockayne syndrome: unusual neuropathological findings and review of the literature. Ann. Neurol. 6,340-348[CrossRef][Medline]
  6. Friedberg, E. C. (1996) Cockayne syndrome—a primary defect in DNA repair, transcription, both or neither?. Bioessays 18,731-738[CrossRef][Medline]
  7. Rapin, I., Lindenbaum, Y., Dickson, D. W., Kraemer, K. H., Robbins, J. H. (2000) Cockayne syndrome and xeroderma pigmentosum. Neurology 55,1442-1449[Abstract/Free Full Text]
  8. Balajee, A. S., Bohr, V. A. (2000) Genomic heterogeneity of nucleotide excision repair. Gene 250,15-30[CrossRef][Medline]
  9. Barrett, S. F., Robbins, J. H., Tarone, R. E., Kraemer, K. H. (1991) Evidence for defective repair of cyclobutane pyrimidine dimers with normal repair of other DNA photoproducts in a transcriptionally active gene transfected into Cockayne syndrome cells. Mutat. Res. 255,281-291[Medline]
  10. Mayne, L. V., Lehmann, A. R. (1982) Failure of RNA synthesis to recover after UV irradiation: an early defect in cells from individuals with Cockayne's syndrome and xeroderma pigmentosum. Cancer Res. 42,1473-1478[Abstract/Free Full Text]
  11. van Hoffen, A., Natarajan, A. T., Mayne, L. V., van Zeeland, A. A., Mullenders, L. H., Venema, J. (1993) Deficient repair of the transcribed strand of active genes in Cockayne's syndrome cells. Nucleic Acids Res. 21,5890-5895[Abstract/Free Full Text]
  12. Venema, J., Mullenders, L. H., Natarajan, A. T., van Zeeland, A. A., Mayne, L. V. (1990) The genetic defect in Cockayne syndrome is associated with a defect in repair of UV-induced DNA damage in transcriptionally active DNA. Proc. Natl. Acad. Sci. USA 87,4707-4711[Abstract/Free Full Text]
  13. Cooper, P. K., Nouspikel, T., Clarkson, S. G., Leadon, S. A. (1997) Defective transcription-coupled repair of oxidative base damage in Cockayne syndrome patients from XP group G. Science 275,990-993[Abstract/Free Full Text]
  14. Le Page, F., Klungland, A., Barnes, D. E., Sarasin, A., Boiteux, S. (2000) Transcription coupled repair of 8-oxoguanine in murine cells: the ogg1 protein is required for repair in nontranscribed sequences but not in transcribed sequences. Proc. Natl. Acad. Sci. USA 97,8397-8402[Abstract/Free Full Text]
  15. Le Page, F., Kwoh, E. E., Avrutskaya, A., Gentil, A., Leadon, S. A., Sarasin, A., Cooper, P. K. (2000) Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB and implications for Cockayne syndrome. Cell 101,159-171[CrossRef][Medline]
  16. Dianov, G., Bischoff, C., Sunesen, M., Bohr, V. A. (1999) Repair of 8-oxoguanine in DNA is deficient in Cockayne syndrome group B cells. Nucleic Acids Res. 27,1365-1368[Abstract/Free Full Text]
  17. Tuo, J., Müftüoglu, M., Chen, C., Jaruga, P., Selzer, R. R., Brosh, R. M., Jr, Rodriguez, H., Dizdaroglu, M., Bohr, V. A. (2001) The Cockayne syndrome group B gene product is involved in general genome base excision repair of 8-hydroxyguanine in DNA. J. Biol. Chem. 276,45772-45779[Abstract/Free Full Text]
  18. Tuo, J., Jaruga, P., Rodriguez, H., Dizdaroglu, M., Bohr, V. A. (2002) The Cockayne syndrome group B gene product is involved in cellular repair of 8-hydroxyadenine in DNA. J. Biol. Chem. 277,30832-30837[Abstract/Free Full Text]
  19. Dizdaroglu, M., Jaruga, P., Rodriguez, H. (2001) Measurement of 8-hydroxy-2'-deoxyguanosine in DNA by high-performance liquid chromatography-mass spectrometry: comparison with measurement by gas chromatography-mass spectrometry. Nucleic Acids Res. 29,E12
  20. Dianov, G., Lindahl, T. (1991) Preferential recognition of I.T base-pairs in the initiation of excision-repair by hypoxanthine-DNA glycosylase. Nucleic Acids Res. 19,3829-3833[Abstract/Free Full Text]
  21. Dizdaroglu, M., Jaruga, P., Birincioglu, M., Rodriguez, H. (2002) Free radical-induced damage to DNA: mechanisms and measurement. Free Radic. Biol. Med. 32,1102-1115[CrossRef][Medline]
  22. Boiteux, S., Gajewski, E., Laval, J., Dizdaroglu, M. (1992) Substrate specificity of the Escherichia coli Fpg (formamidopyrimidine-DNA glycosylase): excision of purine lesions in DNA produced by ionizing radiation or photosensitization. Biochemistry 31,106-110[CrossRef][Medline]
  23. Halliwell, B., Gutteridge, J. M. (1990) Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 186,1-85[CrossRef][Medline]
  24. Wallace, S. S. (2002) Biological consequences of free radical-damaged DNA bases(1,2). Free Radic. Biol. Med. 33,1-14[CrossRef][Medline]
  25. Friedberg, E. C., Walker, G. C., Siede, W. (1995) DNA Repair and Mutagenesis ,42-43 ASM Press Washington D.C..
  26. Lindahl, T., Karran, P., Wood, R. D. (1997) DNA excision repair pathways. Curr. Opin. Genet. Dev. 7,158-169[CrossRef][Medline]
  27. Wood, R. D. (1996) DNA repair in eukaryotes. Annu. Rev. Biochem. 65,135-167[CrossRef][Medline]
  28. Shibutani, S., Takeshita, M., Grollman, A. P. (1991) Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature (London) 349,431-434[CrossRef][Medline]
  29. Le Page, F., Margot, A., Grollman, A. P., Sarasin, A., Gentil, A. (1995) Mutagenicity of a unique 8-oxoguanine in a human Ha-ras sequence in mammalian cells. Carcinogenesis 16,2779-2784[Abstract/Free Full Text]
  30. Kuchino, Y., Mori, F., Kasai, H., Inoue, H., Iwai, S., Miura, K., Ohtsuka, E., Nishimura, S. (1987) Misreading of DNA templates containing 8-hydroxydeoxy-guanosine at the modified base and at adjacent residues. Nature (London) 327,77-79[CrossRef][Medline]
  31. Boiteux, S., Radicella, J. P. (2000) The human OGG1 gene: structure, functions, and its implication in the process of carcinogenesis. Arch. Biochem. Biophys. 377,1-8[CrossRef][Medline]
  32. Tuo, J., Chen, C., Zeng, M., Christiansen, M., Bohr, V. A. (2002) Functional Crosstalk between hOGG1 and the helicase domain of Cockayne syndrome group B protein. DNA Repair 1,913-917[CrossRef][Medline]
  33. Leadon, S. A., Cooper, P. K. (1993) Preferential repair of ionizing radiation-induced damage in the transcribed strand of an active human gene is defective in Cockayne syndrome. Proc. Natl. Acad. Sci. USA 90,10499-10503[Abstract/Free Full Text]
  34. Klein, J. C., Bleeker, M. J., Saris, C. P., Roelen, H. C., Brugghe, H. F., van den, E. H., van der Marel, G. A., van Boom, J. H., Westra, J. G., Kriek, E. (1992) Repair and replication of plasmids with site-specific 8-oxodG and 8-AAFdG residues in normal and repair-deficient human cells. Nucleic Acids Res. 20,4437-4443[Abstract/Free Full Text]
  35. Guschlbauer, W., Duplaa, A. M., Guy, A., Teoule, R., Fazakerley, G. V. (1991) Structure and in vitro replication of DNA templates containing 7,8-dihydro-8-oxoadenine. Nucleic Acids Res. 19,1753-1758[Abstract/Free Full Text]
  36. Kamiya, H., Miura, H., Murata-Kamiya, N., Ishikawa, H., Sakaguchi, T., Inoue, H., Sasaki, T., Masutani, C., Hanaoka, F., Nishimura, S. (1995) 8-Hydroxyadenine (7,8-dihydro-8-oxoadenine) induces misincorporation in in vitro DNA synthesis and mutations in NIH 3T3 cells. Nucleic Acids Res. 23,2893-2899[Abstract/Free Full Text]
  37. Shibutani, S., Bodepudi, V., Johnson, F., Grollman, A. P. (1993) Translesional synthesis on DNA templates containing 8-oxo-7,8-dihydrodeoxyadenosine. Biochemistry 32,4615-4621[CrossRef][Medline]
  38. Tan, X., Grollman, A. P., Shibutani, S. (1999) Comparison of the mutagenic properties of 8-oxo-7,8-dihydro-2'-deoxyadenosine and 8-oxo-7,8-dihydro-2'-deoxyguanosine DNA lesions in mammalian cells. Carcinogenesis 20,2287-2292[Abstract/Free Full Text]
  39. Wang, D., Kreutzer, D. A., Essigmann, J. M. (1998) Mutagenicity and repair of oxidative DNA damage: insights from studies using defined lesions. Mutat. Res. 400,99-115[Medline]
  40. Wood, M. L., Esteve, A., Morningstar, M. L., Kuziemko, G. M., Essigmann, J. M. (1992) Genetic effects of oxidative DNA damage: comparative mutagenesis of 7,8-dihydro-8-oxoguanine and 7,8-dihydro-8-oxoadenine in Escherichia coli. Nucleic Acids Res. 20,6023-6032[Abstract/Free Full Text]
  41. Jaruga, P., Dizdaroglu, M. (1996) Repair of products of oxidative DNA base damage in human cells. Nucleic Acids Res. 24,1389-1394[Abstract/Free Full Text]
  42. Bohr, V. A. (2002) Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells(1,2). Free Radic. Biol. Med. 32,804-812[CrossRef][Medline]
  43. de Boer, J., Andressoo, J. O., de Wit, J., Huijmans, J., Beems, R. B., van Steeg, H., Weeda, G., van der Horst, G. T., van Leeuwen, W., Themmen, A. P., et al (2002) Premature aging in mice deficient in DNA repair and transcription. Science 296,1276-1279[Abstract/Free Full Text]
  44. Kipling, D., Faragher, R. G. (1997) Progeroid syndromes: probing the molecular basis of aging?. Mol. Pathol. 50,234-241[Abstract/Free Full Text]
  45. Hayashi, M., Itoh, M., Araki, S., Kumada, S., Shioda, K., Tamagawa, K., Mizutani, T., Morimatsu, Y., Minagawa, M., Oda, M. (2001) Oxidative stress and disturbed glutamate transport in hereditary nucleotide repair disorders. J. Neuropathol. Exp. Neurol. 60,350-356[Medline]
  46. Tuo, J., Liu, L., Poulsen, H. E., Weimann, A., Svendsen, O., Loft, S. (2000) Importance of guanine nitration and hydroxylation in DNA in vitro and in vivo. Free Radic. Biol. Med. 29,147-155[CrossRef][Medline]
  47. Mallery, D. L., Tanganelli, B., Colella, S., Steingrimsdottir, H., van Gool, A. J., Troelstra, C., Stefanini, M., Lehmann, A. R. (1998) Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome. Am. J. Hum. Genet. 62,77-85[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Mol. Cell. Biol.Home page
J.-O. Andressoo, G. Weeda, J. de Wit, J. R. Mitchell, R. B. Beems, H. van Steeg, G. T. J. van der Horst, and J. H. Hoeijmakers
An Xpb Mouse Model for Combined Xeroderma Pigmentosum and Cockayne Syndrome Reveals Progeroid Features upon Further Attenuation of DNA Repair
Mol. Cell. Biol., March 1, 2009; 29(5): 1276 - 1290.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
S. Z. Imam, F. E. Indig, W.-H. Cheng, S. P. Saxena, T. Stevnsner, D. Kufe, and V. A. Bohr
Cockayne syndrome protein B interacts with and is phosphorylated by c-Abl tyrosine kinase
Nucleic Acids Res., August 1, 2007; 35(15): 4941 - 4951.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
H.-K. Wong, M. Muftuoglu, G. Beck, S. Z. Imam, V. A. Bohr, and D. M. Wilson III
Cockayne syndrome B protein stimulates apurinic endonuclease 1 activity and protects against agents that introduce base excision repair intermediates
Nucleic Acids Res., June 12, 2007; (2007) gkm404v1.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
T. G. M. F. Gorgels, I. van der Pluijm, R. M. C. Brandt, G. A. Garinis, H. van Steeg, G. van den Aardweg, G. H. Jansen, J. M. Ruijter, A. A. B. Bergen, D. van Norren, et al.
Retinal Degeneration and Ionizing Radiation Hypersensitivity in a Mouse Model for Cockayne Syndrome
Mol. Cell. Biol., February 15, 2007; 27(4): 1433 - 1441.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. R. Laposa, E. J. Huang, and J. E. Cleaver
Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice
PNAS, January 23, 2007; 104(4): 1389 - 1394.
[Abstract] [Full Text] [PDF]

Home page
 Cereb CortexHome page
R. Narasimhaiah, A. Tuchman, S. L. Lin, and J. R. Naegele
Oxidative Damage and Defective DNA Repair is Linked to Apoptosis of Migrating Neurons and Progenitors During Cerebral Cortex Development in Ku70-Deficient Mice
Cereb Cortex, June 1, 2005; 15(6): 696 - 707.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. D'Errico, M. Teson, A. Calcagnile, T. Nardo, N. De Luca, C. Lazzari, S. Soddu, G. Zambruno, M. Stefanini, and E. Dogliotti
Differential Role of Transcription-Coupled Repair in UVB-Induced Response of Human Fibroblasts and Keratinocytes
Cancer Res., January 15, 2005; 65(2): 432 - 438.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
G. Spivak
The many faces of Cockayne syndrome
PNAS, October 26, 2004; 101(43): 15273 - 15274.
[Full Text] [PDF]

Home page
 Genes Dev.Home page
C. L. Peterson and J. Cote
Cellular machineries for chromosomal DNA repair
Genes & Dev., March 15, 2004; 18(6): 602 - 616.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by TUO, J.
Right arrow Articles by DIZDAROGLU, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by TUO, J.
Right arrow Articles by DIZDAROGLU, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS