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PubMed2006

Comparison in a laboratory model between the performance of a urinary closed system bag with double non-return valve and that of a single valve system.

BACKGROUND: Catheter-associated urinary tract infection is the most common nosocomial infection in clinical settings. For bacteria ascending to the bladder the most common route is the extraluminal, but the intraluminal route also plays a role. For this reason, we compared two urinary closed system bags (CSB), one with a double and the other with a single non-return valve (NRV), in a laboratory setting in order to establish their ability to prevent or delay the ascent of bacteria from the drainage bag to the bladder. PATIENTS AND METHODS: The tests were performed in two microbiological laboratories (Copenhagen (C), Denmark and Freiburg (F), Germany). These were blinded to each other. A urinary tract model using artificial urine was set up. Two sets of ten drainage bags each with a double NRV (CSB A), and two sets of ten drainage bags each with a single NRV (CSB B) were inoculated with Escherichia coli (F: ATCC 25922; C: clinical strain). Daily samples were taken from two drainage ports on each system - one above the NRV (Port I), the other above the top of the artificial bladder (Port II). Time till E. coli was detected at the drainage ports (time to positivity) was measured. Colonization of the 'bladder' was defined as time to positivity at Port II. RESULTS: No significant differences in time to positivity at Port I (median 9.0, range: 6-12 for CSB B vs median 9.5 days, range: 6-13 for CSB A) were observed between the two systems. However, substantial differences were seen between the two systems in time to positivity at Port II: Port II on the bladder model using CSB B became positive after a median of 14.0 days (range: 10-22), whereas Port II of the model using CSB A only became positive after 21.5 days (range: 13-24). This amounts to a highly significant difference of 7.5 days (p = 0.0001) in the mean. CONCLUSION: Under laboratory conditions, colonization of the 'bladder' was significantly delayed when the CSB with a double NRV was used in comparison to the results obtained from the single NRV-system. Clinical trials should be conducted to investigate whether the urinary CSB with the double NRV has the ability to prevent (or to delay the onset of) catheter-associated urinary tract infection.

Equipment Contamination↗
PubMed2000

Role of the ATPase domain of the Cockayne syndrome group B protein in UV induced apoptosis.

Cockayne syndrome (CS) is a human autosomal recessive disorder characterized by many neurological and developmental abnormalities. CS cells are defective in the transcription coupled repair (TCR) pathway that removes DNA damage from the transcribed strand of active genes. The individuals suffering from CS do not generally develop cancer but show increased neurodegeneration. Two genetic complementation groups (CS-A and CS-B) have been identified. The lack of cancer formation in CS may be due to selective elimination of cells containing DNA damage by a suicidal pathway. In this study, we have evaluated the role of the CSB gene in UV induced apoptosis in human and hamster cells. The hamster cell line UV61 carries a mutation in the homolog of the human CSB gene. We show that both human CS-B and hamster UV61 cells display increased apoptotic response following UV exposure compared with normal cells. The increased sensitivity of UV61 cells to apoptosis is complemented by the transfection of the wild type human CSB gene. In order to determine which functional domain of the CSB gene participates in the apoptotic pathway, we constructed stable cell lines with different CSB domain disruptions. UV61 cells were stably transfected with the human CSB cDNA containing a point mutation in the highly conserved glutamic acid residue in ATPase motif II. This cell line (UV61/ pc3.1-CSBE646Q) showed the same increased apoptosis as the UV61 cells. In contrast, cells containing a deletion in the acidic domain at the N-terminal end of the CSB protein had no effect on apoptosis. This indicates that the integrity of the ATPase domain of CSB protein is critical for preventing the UV induced apoptotic pathway. In primary human CS-B cells, the induction and stabilization of the p53 protein seems to correlate with their increased apoptotic potential. In contrast, no change in the level of either p53 or activation of mdm2 protein by p53 was observed in hamster UV61 cells after UV exposure. This suggests that the CSB dependent apoptotic pathway can occur independently of the transactivation potential of p53 in hamster cells.

Adenosine Triphosphatases↗
PubMed1998

A conserved sequence block in murine and human T cell receptor (TCR) Jalpha region is a composite element that enhances TCR alpha enhancer activity and binds multiple nuclear factors.

A conserved sequence block (CSB) located in a noncoding region of the mouse and human TCR alpha/delta loci, showing six differences over 125 nucleotide positions (95% similar), was subjected to detailed analyses in this study. Transient transfection results showed that the CSB-containing element in conjunction with the TCR alpha enhancer up-regulated the alpha enhancer activity, whereas no enhancer activity was detected when CSB alone was assayed. In vitro occupancy analyses of CSB by nuclear factors reveal the existence of an unexpectedly intricate network of CSB-protein and protein-protein interactions. Lymphoid-specific as well as T-lineage-specific nuclear factors are involved to differentially form CSB-bound complexes in extracts of various tissues and cell lines. Liver was shown to contain factor(s) sequestering thymic CSB-binding factors. Furthermore, the putative binding sites for transcription factors known to be important for lymphoid-lineage development are present in CSB and are targeted by nuclear factors. On the basis of these results, we propose that the CSB element may play a role in shaping the chromatin structure by which the accessibility of TCR alpha/delta loci to the recombinase complex and/or to the transcriptional apparatus can be controlled.

Animals↗
PubMed1997

The Cockayne syndrome B protein, involved in transcription-coupled DNA repair, resides in an RNA polymerase II-containing complex.

Transcription-coupled repair (TCR), a subpathway of nucleotide excision repair (NER) defective in Cockayne syndrome A and B (CSA and CSB), is responsible for the preferential removal of DNA lesions from the transcribed strand of active genes, permitting rapid resumption of blocked transcription. Here we demonstrate by microinjection of antibodies against CSB and CSA gene products into living primary fibroblasts, that both proteins are required for TCR and for recovery of RNA synthesis after UV damage in vivo but not for basal transcription itself. Furthermore, immunodepletion showed that CSB is not required for in vitro NER or transcription. Its central role in TCR suggests that CSB interacts with other repair and transcription proteins. Gel filtration of repair- and transcription-competent whole cell extracts provided evidence that CSB and CSA are part of large complexes of different sizes. Unexpectedly, there was no detectable association of CSB with several candidate NER and transcription proteins. However, a minor but significant portion (10-15%) of RNA polymerase II was found to be tightly associated with CSB. We conclude that within cell-free extracts, CSB is not stably associated with the majority of core NER or transcription components, but is part of a distinct complex involving RNA polymerase II. These findings suggest that CSB is implicated in, but not essential for, transcription, and support the idea that Cockayne syndrome is due to a combined repair and transcription deficiency.

Cockayne Syndrome↗
PubMed2002

Differential requirement for the ATPase domain of the Cockayne syndrome group B gene in the processing of UV-induced DNA damage and 8-oxoguanine lesions in human cells.

Cockayne syndrome (CS) is a rare inherited human genetic disorder characterized by UV sensitivity, developmental abnormalities and premature aging. The cellular and molecular phenotypes of CS include increased sensitivity to oxidative and UV-induced DNA lesions. The CSB protein is thought to play a pivotal role in transcription-coupled repair and CS-B cells are defective in the repair of the transcribed strand of active genes, both after exposure to UV and in the presence of oxidative DNA lesions. A previous study has indicated that a conserved helicase ATPase motif II residue is essential for the function of the CSB protein in responding to UV-induced DNA damage in a hamster cell line. Due to the limitations in studying a complex human disorder in another species, this study introduced the site-directed mutation of the ATPase motif II in the human CSB gene in an isogenic human cell line. The CSB mutant allele was tested for genetic complementation of UV-sensitive phenotypes in the human CS-B cell line CS1AN.S3.G2. In addition, the incision of an 8-oxoguanine lesion by extracts of the CS-B cell lines stably transfected with the wild-type or ATPase mutant CSB gene has been investigated. The ATPase motif II point mutation (E646Q) abolished the function of the CSB protein to complement the UV-sensitive phenotypes of survival, RNA synthesis recovery and apoptosis. Interestingly, whole-cell extract prepared from these mutant cells retained wild-type incision activity on an oligonucleotide containing a single 8-oxoguanine lesion, whereas the absence of the CSB gene altogether resulted in reduced incision activity relative to wild-type. These results suggest damage-specific functional requirements for CSB in the repair of UV-induced and oxidative lesions in human cells. The transfection of the mutant or wild-type CSB gene into the CS1AN.S3.G2 cells did not alter the expression of the subset of genes examined by cDNA array analysis.

Adenosine Triphosphatases↗
PubMed2000

ATP-dependent chromatin remodeling by the Cockayne syndrome B DNA repair-transcription-coupling factor.

The Cockayne syndrome B protein (CSB) is required for coupling DNA excision repair to transcription in a process known as transcription-coupled repair (TCR). Cockayne syndrome patients show UV sensitivity and severe neurodevelopmental abnormalities. CSB is a DNA-dependent ATPase of the SWI2/SNF2 family. SWI2/SNF2-like proteins are implicated in chromatin remodeling during transcription. Since chromatin structure also affects DNA repair efficiency, chromatin remodeling activities within repair are expected. Here we used purified recombinant CSB protein to investigate whether it can remodel chromatin in vitro. We show that binding of CSB to DNA results in an alteration of the DNA double-helix conformation. In addition, we find that CSB is able to remodel chromatin structure at the expense of ATP hydrolysis. Specifically, CSB can alter DNase I accessibility to reconstituted mononucleosome cores and disarrange an array of nucleosomes regularly spaced on plasmid DNA. In addition, we show that CSB interacts not only with double-stranded DNA but also directly with core histones. Finally, intact histone tails play an important role in CSB remodeling. CSB is the first repair protein found to play a direct role in modulating nucleosome structure. The relevance of this finding to the interplay between transcription and repair is discussed.

Adenosine Triphosphate↗
PubMed1992

Effect of heating on nutritional quality of conventional and Kunitz trypsin inhibitor-free soybeans.

Five 10-day chick growth experiments and an amino acid digestibility assay were conducted to assess the effect of steam heating on in vivo protein quality of raw, full-fat Kunitz trypsin inhibitor-free soybeans (KFSB) compared with raw, conventional full-fat soybeans (CSB). Protein solubility in .2% KOH was also evaluated as an in vitro test of in vivo protein quality for underprocessed CSB. The CSB and KFSB were autoclaved for 0, 3, 6, 9, 12, 15, 18, or 21 min at 121 C and 124 kPa. The soybeans were then fed to 8- or 9-day-old chicks as the sole source of protein in dextrose and soybean diets containing 23% protein. Growth performance of chicks fed raw KFSB was superior to that of chicks fed raw CSB. Growth performance of chicks fed autoclaved KFSB or CSB increased and pancreas weight (percentage of body weight) decreased as autoclaving time increased. Slightly less autoclaving time was consistently required to achieve maximum chick performance for KFSB compared with CSB. Less autoclaving time was also required to obtain maximum digestibility of amino acids in KFSB compared with CSB. Urease activity of the soybeans decreased as autoclaving time increased, whereas protein solubility in .2% KOH for CSB did not change consistently in response to heating time. The results of the present study indicate that raw KFSB must be heated to obtain maximum protein quality for chicks and that protein solubility in KOH is not a sensitive indicator of underprocessing of CSB soybeans.

Amino Acids↗
PubMed2000

Impact of global genome repair versus transcription-coupled repair on ultraviolet carcinogenesis in hairless mice.

The nucleotide excision repair (NER) system is comprised of two subpathways, i.e., transcription-coupled repair (TCR) and global genome repair (GGR). To establish the relative importance of TCR and GGR for UV effects on the skin, we have used hairless knockout mouse strain lacking either TCR (CSB -/-) or GGR (XPC -/-). In single exposure experiments, we found that CSB -/- mice have a 7-16 times higher susceptibility to sunburn than XPC -/- mice and than heterozygous (+/-) and wild-type (+/+) controls. Exposure to 80 J/m2 UV radiation (i.e., suberythemogenic in CSB -/-) on 10 consecutive days gives rise to epidermal hyperplasia in CSB -/- and XPC -/-, whereas repair-proficient controls do not show epidermal hyperplasia from these exposures. In addition, CSB -/- mice develop marked parakeratosis, whereas XPC -/- mice and controls do not. Under continued exposure to this daily dose, squamous cell carcinomas appear in CSB -/-, XPC -/-, and in the control groups, whereas only in the CSB -/- animals is a fairly high number of benign papillomas also found. The median latency time of squamous cell carcinomas (diameters > or = 1 mm) is 84 days for the XPC -/- mice, 115 days for the CSB -/- mice, and 234-238 days for the heterozygous and wild-type control groups. These results indicate that GGR is more important than TCR in protection against UV-induced carcinomas of the skin but not against other UV effects such as sunburn, epidermal thickening, scaling of the stratum corneum, and development of papillomas. These results also indicate that GGR capacity may serve as a better predictor for skin cancer susceptibility than sensitivity to sunburn. The relative cancer susceptibilities of GGR- and TCR-deficient skin could well depend on the balance between an increased mutation rate and the presence (in CSB -/-) or lack (in XPC -/-) of a compensatory apoptotic response.

Animals↗
PubMed1998

Appetitive and consummatory male sexual behavior in Japanese quail are differentially regulated by subregions of the preoptic medial nucleus.

Central testosterone aromatization is required for the activation of both appetitive (ASB) and consummatory (CSB) male sexual behavior in Japanese quail. There are two major clusters of aromatase immunoreactive (ARO-ir) cells in the rostral forebrain; these outline the nucleus preopticus medialis (POM) and the nucleus striae terminalis (BST). We investigated the role of these nuclei in the regulation of ASB and CSB. Appetitive male sexual behavior was measured with the use of a learned social proximity procedure that quantified the time spent by a male in front of a window with a view of a female who was subsequently released into the cage, providing an opportunity for CSB. Males first acquired the response and then received bilateral electrolytic lesions aimed at the POM or BST, followed by retesting for ASB and CSB. Brain sections were stained for ARO-ir, and lesions to the two ARO-ir cell groups were quantitatively characterized. Lesions damaging the POM completely abolished CSB and also significantly decreased ASB. Lesions of the rostral BST had no effect on ASB, but moderately decreased CSB. Detailed anatomical analysis revealed that lesions of a subdivision of the POM just rostral to the anterior commissure specifically impair CSB, whereas lesions that are more rostral to this subdivision induce a severe deficit in ASB. These data indicate that different subregions of the POM regulate ASB and CSB in a somewhat independent manner, whereas the BST is only important in the regulation of CSB.

Animals↗
PubMed2007

Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice.

Cockayne syndrome (CS) is a rare recessive childhood-onset neurodegenerative disease, characterized by a deficiency in the DNA repair pathway of transcription-coupled nucleotide excision repair. Mice with a targeted deletion of the CSB gene (Csb-/-) exhibit a much milder ataxic phenotype than human patients. Csb-/- mice that are also deficient in global genomic repair [Csb-/-/xeroderma pigmentosum C (Xpc)-/-] are more profoundly affected, exhibiting whole-body wasting, ataxia, and neural loss by postnatal day 21. Cerebellar granule cells demonstrated high TUNEL staining indicative of apoptosis. Purkinje cells, identified by the marker calbindin, were severely depleted and, although not TUNEL-positive, displayed strong immunoreactivity for p53, indicating cellular stress. A subset of animals heterozygous for Csb and Xpc deficiencies was more mildly affected, demonstrating ataxia and Purkinje cell loss at 3 months of age. Mouse, Csb-/-, and Xpc-/- embryonic fibroblasts each exhibited increased sensitivity to UV light, which generates bulky DNA damage that is a substrate for excision repair. Whereas Csb-/-/Xpc-/- fibroblasts were more UV-sensitive than either single knockout, double-heterozygote fibroblasts had normal UV sensitivity. Csb-/- mice crossed with a strain defective in base excision repair (Ogg1) demonstrated no enhanced neurodegenerative phenotype. Complete deficiency in nucleotide excision repair therefore renders the brain profoundly sensitive to neurodegeneration in specific cell types of the cerebellum, possibly because of unrepaired endogenous DNA damage that is a substrate for nucleotide but not base excision repair.

Animals↗
PubMed2001

The Cockayne Syndrome group B gene product is involved in general genome base excision repair of 8-hydroxyguanine in DNA.

Cockayne Syndrome (CS) is a human genetic disorder with two complementation groups, CS-A and CS-B. The CSB gene product is involved in transcription-coupled repair of DNA damage but may participate in other pathways of DNA metabolism. The present study investigated the role of different conserved helicase motifs of CSB in base excision repair. Stably transformed human cell lines with site-directed CSB mutations in different motifs within its putative helicase domain were established. We find that CSB null and helicase motif V and VI mutants had greater sensitivity than wild type cells to gamma-radiation. Whole cell extracts from CSB null and motif V/VI mutants had lower activity of 8-hydroxyguanine incision in DNA than wild type cells. Also, 8-hydroxyguanine accumulated more in CSB null and motif VI mutant cells than in wild type cells after exposure to gamma-radiation. We conclude that a deficiency in general genome base excision repair of selective modified DNA base(s) might contribute to CS pathogenesis. Furthermore, whereas the disruption of helicase motifs V or VI results in a CSB phenotype, mutations in other helicase motifs do not cause this effect. The biological functions of CSB in different DNA repair pathways may be mediated by distinct functional motifs of the protein.

Amino Acid Sequence↗
PubMed2005

The Cockayne syndrome group B protein is a functional dimer.

Cockayne syndrome (CS) is a rare inherited human genetic disorder characterized by developmental abnormalities, UV sensitivity, and premature aging. The CS group B (CSB) protein belongs to the SNF2-family of DNA-dependent ATPases and is implicated in transcription elongation, transcription coupled repair, and base excision repair. It is a DNA stimulated ATPase and remodels chromatin in vitro. We demonstrate for the first time that full-length CSB positively cooperates in ATP hydrolysis as a function of protein concentration. We have investigated the quaternary structure of CSB using a combination of protein-protein complex trapping experiments and gel filtration, and found that CSB forms a dimer in solution. Chromatography studies revealed that enzymatically active CSB has an apparent molecular mass of approximately 360 kDa, consistent with dimerization of CSB. Importantly, in vivo protein cross-linking showed the presence of the CSB dimer in the nucleus of HeLa cells. We further show that dimerization occurs through the central ATPase domain of the protein. These results have implications for the mechanism of action of CSB, and suggest that other SNF2-family members might also function as dimers.

Adenosine Triphosphatases↗
PubMed1992

Sulfonic acid dyes: inhibition of the human immunodeficiency virus and mechanism of action.

Over 50 different commercially available sulfonic acid-containing dyes were analyzed for their ability to prevent HIV-1-induced cell killing and in inhibiting HIV-1 replication. Compounds of remarkably similar structure, but with differing patterns of sulfonic acid group substitutions, had a wide range of potency in inhibiting HIV-1. Chicago sky blue (CSB) was highly effective in the inhibition of HIV-1 with less toxicity to CEM-SS cells than most of the other sulfonated dyes tested. Synthesis of CSB was undertaken to produce a product greater than 98% pure and this compound was used to elucidate the possible mechanisms by which this class of structurally related compounds inhibits HIV-1. Addition of CSB to cells infected at high multiplicity at any time up to 24 h after infection, unlike dideoxycytidine (ddC) or oxathiin carboxanilide (OC), inhibited HIV-1-induced cell killing. Other postinfection time course studies revealed that CSB had to be present for 24 h or longer immediately after infection to be protective. Virus binding to cells occurred in the presence of CSB, but the requirement for virion envelope-cell membrane fusion was delayed. CSB was a potent inhibitor of the reverse transcriptase (RT) of both HIV-1 and HIV-2, although it was less active against HIV-2 in a cell killing-based assay. CSB also inhibited Rauscher and LP-BM5 murine leukemia viruses. CSB appears to disrupt the interaction between viral proteins and cell membranes, both in the fusion step early in the infection cycle and in the development of syncytia in the late stages of virus infection.

Antiviral Agents↗
PubMed2001

A conserved sequence block in the murine and human T cell receptor Jalpha loci interacts with developmentally regulated nucleoprotein complexes in vitro and associates with GATA-3 and octamer-binding factors in vivo.

A highly conserved sequence block (CSB) located in the mouse and human T cell receptor (TCR) Jalpha loci is recognized by tissue-specific factors and up-regulates TCR alpha enhancer activity. In this study, the properties of CSB-interacting factors were further explored to decipher the function of this cis-acting element. Thymocytes corresponding to different developmental stages were found capable of forming differential CSB-nucleoprotein complexes. Pronounced changes in the CSB-complex-forming activity were observed during the transition from double-negative to double-positive thymocytes. Furthermore, we showed that transcription factors Oct-1, Oct-2 and GATA-3 interacted with CSB both in vitro, as evidenced by electrophoretic mobility shift assays, and in vivo, as demonstrated by chromatin immunoprecipitation assays in mouse thymus. Importantly, we also demonstrated that GATA-3 associated in vivo with TCR alpha enhancer, the activity of which is known to be required in regulating chromatin accessibility to the V(D)J recombinase. Thus, CSB may temporally regulate local chromatin structure and help to spread TCR alpha enhancer activity over the entire 70-kb Jalpha locus by forming developmentally regulated CSB-nucleoprotein complexes and by interacting with other cis-regulatory element-nucleoprotein complexes present within the TCR alpha / delta locus.

Animals↗
PubMed2003

Possible involvement of energy metabolism in the change of cytoplasm organization induced by a protein phosphatase inhibitor, calyculin A, in root hair cells of Limnobium stoloniferum.

In root hair cells of Limnobium stoloniferum, transvacuolar strands disperse and cytoplasmic spherical bodies (CSBs) emerge upon treatment with a protein phosphatase inhibitor, calyculin A (CA), whose effects were previously shown to be canceled by simultaneous treatment of the cells with a nonselective protein kinase inhibitor, K-252a. CSB formation is also suppressed by latrunculin B (LB) or cytochalasin D, actin filament depolymerization drugs, or 2,3-butanedione monoxime, an inhibitor of myosin activity. To confirm the involvement of myosin activity in CSB formation induced by CA, we examined the effect of an inhibitor of energy metabolism, NaN3, on CSB formation in root hair cells pretreated simultaneously with CA and LB. In the presence of CA-LB, CSB formation was suppressed due to the depolymerization of actin filaments. When these drugs were removed, the actin filaments recovered and CSBs emerged even in the presence of K-252a. These results indicated that the phosphorylation level in the cells is elevated during the CA-LB treatment and that a phosphorylation level sufficient for the CSB formation was sustained even after CA removal. On the other hand, CSB formation after simultaneous treatment with CA and LB was significantly suppressed in the presence of NaN3. In such cells, actin filament bundles recovered, although their organization was random. The present and previous results suggested that myosin activity is necessary for CSB formation induced by CA, and that myosin regulated by phosphorylation-dephosphorylation is implicated in the organization of the actin cytoskeleton in root hair cells.

Actins↗
PubMed1992

Comparative results of carotid-subclavian bypass and axillo-axillary bypass in patients with symptomatic subclavian disease.

The results of 26 carotid-subclavian bypass (CSB) and 17 axillo-axillary bypass (AAB) procedures, performed to treat symptomatic lesions of the proximal subclavian artery, were reviewed. Nine graft failures (seven CSB and two AAB) occurred (mean follow-up: CSB = 60.5 +/- 41 months; AAB = 67.8 +/- 48 months). All CSB graft thromboses were observed in patients with an associated ipsilateral carotid lesion, surgically treated or not (p less than 0.05). Cumulative 5- and 10-year patency rates were 78.3 and 62.9% for the CSB group and 87.9% for the AAB group (N.S.). In patients with an associated ipsilateral carotid lesion, 5- and 10-year patency rates were 66.0% and 40.8% for the CSB group and 100% for the AAB group (p less than 0.05). Both the surgical procedures were safe and effective with excellent results in terms of operative mortality, major morbidity and long-term patency. CSB is the procedure of choice for the treatment of proximal subclavian artery disease for its physiological characteristics and for graft shortness. However AAB must be considered a suitable alternative and preferred when a concomitant ipsilateral carotid lesion is present. Recurrence of carotid stenosis or carotid lesion progression may cause the carotid-subclavian failure.

Aged↗
PubMed2002

Mitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B.

Reactive oxygen species, which are prevalent in mitochondria, cause oxidative DNA damage including the mutagenic DNA lesion 7,8-dihydroxyguanine (8-oxoG). Oxidative damage to mitochondrial DNA has been implicated as a causative factor in a wide variety of degenerative diseases, and in cancer and aging. 8-oxoG is repaired efficiently in mammalian mitochondrial DNA by enzymes in the base excision repair pathway, including the 8-oxoguanine glycosylase (OGG1), which incizes the lesion in the first step of repair. Cockayne syndrome (CS) is a segmental premature aging syndrome in humans that has two complementation groups, CSA and CSB. Previous studies showed that CSB-deficient cells have reduced capacity to repair 8-oxoG. This study examines the role of the CSB gene in regulating repair of 8-oxoG in mitochondrial DNA in human and mouse cells. 8-oxoG repair was measured in liver cells from CSB deficient mice and in human CS-B cells carrying expression vectors for wild type or mutant forms of the human CSB gene. For the first time we report that CSB stimulates repair of 8-oxoG in mammalian mitochondrial DNA. Furthermore, evidence is presented to support the hypothesis that wild type CSB regulates expression of OGG1.

Amino Acid Sequence↗
PubMed2002

The cockayne syndrome group B gene product is involved in cellular repair of 8-hydroxyadenine in DNA.

Cockayne syndrome (CS) is a human disease characterized by sensitivity to sunlight, severe neurological abnormalities, and accelerated aging. CS has two complementation groups, CS-A and CS-B. The CSB gene encodes the CSB protein with 1493 amino acids. We previously reported that the CSB protein is involved in cellular repair of 8-hydroxyguanine, an abundant lesion in oxidatively damaged DNA and that the putative helicase motif V/VI of the CSB may play a role in this process. The present study investigated the role of the CSB protein in cellular repair of 8-hydroxyadenine (8-OH-Ade), another abundant lesion in oxidatively damaged DNA. Extracts of CS-B-null cells and mutant cells with site-directed mutation in the motif VI of the putative helicase domain incised 8-hydroxyadenine in vitro less efficiently than wild type cells. Furthermore, CS-B-null and motif VI mutant cells accumulated more 8-hydroxyadenine in their genomic DNA than wild type cells after exposure to gamma-radiation at doses of 2 or 5 Gy. These results suggest that the CSB protein contributes to cellular repair of 8-OH-Ade and that the motif VI of the putative helicase domain of CSB is required for this activity.

Adenine↗