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1.
Developmental Defects and Male Sterility in Mice Lacking the Ubiquitin-Like DNA Repair Gene mHR23B
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Jessica M. Y. Ng Harry Vrieling Kaoru Sugasawa Marja P. Ooms J. Anton Grootegoed Jan T. M. Vreeburg Pim Visser Rudolph B. Beems Theo G. M. F. Gorgels Fumio Hanaoka Jan H. J. Hoeijmakers Gijsbertus T. J. van der Horst 《Molecular and cellular biology》2002,22(4):1233-1245
mHR23B encodes one of the two mammalian homologs of Saccharomyces cerevisiae RAD23, a ubiquitin-like fusion protein involved in nucleotide excision repair (NER). Part of mHR23B is complexed with the XPC protein, and this heterodimer functions as the main damage detector and initiator of global genome NER. While XPC defects exist in humans and mice, mutations for mHR23A and mHR23B are not known. Here, we present a mouse model for mHR23B. Unlike XPC-deficient cells, mHR23B(-/-) mouse embryonic fibroblasts are not UV sensitive and retain the repair characteristics of wild-type cells. In agreement with the results of in vitro repair studies, this indicates that mHR23A can functionally replace mHR23B in NER. Unexpectedly, mHR23B(-/-) mice show impaired embryonic development and a high rate (90%) of intrauterine or neonatal death. Surviving animals display a variety of abnormalities, including retarded growth, facial dysmorphology, and male sterility. Such abnormalities are not observed in XPC and other NER-deficient mouse mutants and point to a separate function of mHR23B in development. This function may involve regulation of protein stability via the ubiquitin/proteasome pathway and is not or only in part compensated for by mHR23A. 相似文献
2.
Relative levels of the two mammalian Rad23 homologs determine composition and stability of the xeroderma pigmentosum group C protein complex 总被引:1,自引:0,他引:1
Okuda Y Nishi R Ng JM Vermeulen W van der Horst GT Mori T Hoeijmakers JH Hanaoka F Sugasawa K 《DNA Repair》2004,3(10):1285-1295
Mammalian cells express two Rad23 homologs, HR23A and HR23B, which have been implicated in regulation of proteolysis via the ubiquitin/proteasome pathway. Recently, the proteins have been shown to stabilize xeroderma pigmentosum group C (XPC) protein that is involved in DNA damage recognition for nucleotide excision repair (NER). Because the vast majority of XPC forms a complex with HR23B rather than HR23A, we investigated possible differences between the two Rad23 homologs in terms of their effects on the XPC protein. In wild-type mouse embryonic fibroblasts (MEFs), endogenous XPC was found to be relatively stable, while its steady-state level and stability appeared significantly reduced by targeted disruption of the mHR23B gene, but not by that of mHR23A. Loss of both mHR23 genes caused a strong further reduction of the XPC protein level. Quantification of the two mHR23 proteins revealed that in normal cells mHR23B is actually approximately 10 times more abundant than mHR23A. In addition, overexpression of mHR23A in the mHR23A/B double knock out cells restored not only the steady-state level and stability of the XPC protein, but also cellular NER activity to near wild-type levels. These results indicate that the two Rad23 homologs are largely functionally equivalent in NER, and that the difference in expression levels explains for a major part the difference in complex formation with as well as stabilization effects on XPC. 相似文献
3.
Nucleotide excision repair (NER) removes many different types of DNA lesions. Most NER proteins are indispensable for repair. In contrast, the yeast Rad23 represents a class of accessory NER proteins, without which NER activity is reduced but not eliminated. In mammals, the complex of HR23B (Rad23 homolog) and XPC (yeast Rad4 homolog) has been suggested to function in the damage recognition step of NER. However, the precise function of Rad23 or HR23B in NER remains unknown. Recently, it was suggested that the primary function of RAD23 protein in NER is its stabilization of XPC protein. Here, we tested the significance of Rad23-mediated Rad4 stabilization in NER, and analyzed the repair and biochemical activities of purified yeast Rad23 protein. Cellular Rad4 was indeed stabilized by Rad23 in the absence of DNA damage. Persistent overexpression of Rad4 in rad23 mutant cells, however, largely failed to complement the ultraviolet sensitivity of the mutant. Consistently, deficient NER in rad23 mutant cell extracts could not be complemented by purified Rad4 protein in vitro. In contrast, partial complementation was observed with purified Rad23 protein. Specific complementation to the level of wild-type repair was achieved by adding purified Rad23 together with small amounts of Rad4 protein to rad23 mutant cell extracts. Purified Rad23 protein was unable to bind to DNA, but stimulated the binding activity of purified Rad4 protein to N-acetyl-2-aminofluorene-damaged DNA. These results support two roles of Rad23 protein in NER: (i) its direct participation in the repair biochemistry, possibly due to its stimulatory activity on Rad4-mediated damage binding/recognition; and (ii) its stabilization of cellular Rad4 protein. 相似文献
4.
Loss of function of the Wfs1 gene causes Wolfram syndrome, a rare multisystem degenerative disorder. Mutant mice with targeted
Wfs1 gene disruption (Wfs1 KO) display morphological and behavioral impairments that are not well understood. The present
study aimed to investigate the striatal dopamine output of wild-type, heterozygous, and homozygous Wfs1 null-mutant mice using
in vivo microdialysis technique. The baseline dopamine output in striatum was similar in all three animal groups. The application
of 100 mM [K+]-rich modified Ringer solution caused in homozygous Wfs1 mutant mice an increase of dopamine output by 400%, while in wild-type
and heterozygous animals, the increase of the dopamine output yielded up to 1,200%. In sum, the homozygous Wfs1 mutant mice
(AUC0–3 = 0.212 nM/μl h) show significantly decreased striatal dopamine output in response to high-concentration [K+] challenge as compared with wild-type or heterozygous Wfs1 mutant conspecifics (AUC0–3 = 0.427 and 0.505 nM/μl h, respectively). This could explain at least some of the behavioral alterations in Wfs1 mutant mice. 相似文献
5.
Daphne M. Y. Cheah Yolanda J. Deal Paul F. A. Wright Nicole E. Buck Chung Wo Chow Julian F. B. Mercer Katrina J. Allen 《Biometals》2007,20(5):751-757
Wilson’s disease carriers constitute 1% of the human population. It is unknown whether Wilson’s disease carriers are at increased
susceptibility to copper overload when exposed to chronically high levels of ingested copper. This study investigated the
effect of chronic excess copper in drinking water on the heterozygous form of the Wilson's disease mouse model – the toxic
milk (tx) mouse. Mice were provided with drinking water containing 300 mg/l copper for 4–7, 8–11, 12–15 or 16–20 months. At the completion
of the study liver, spleen, kidney and brain tissue were analyzed by atomic absorption spectroscopy to determine copper concentration.
Plasma ceruloplasmin oxidase activity and liver histology were also assessed. Chronic copper loading resulted in significantly
increased liver copper in both tx heterozygous and tx homozygous mice, while wild type mice were resistant to the effects of copper loading. Copper loading effects were greatest
in tx homozygous mice, with increased extrahepatic copper deposition in spleen and kidney – an effect absent in heterozygote and
wild type mice. Although liver histology in homozygous mice was markedly abnormal, no histological differences were noted
between heterozygous and wild type mice with copper loading. Tx heterozygous mice have a reduced ability to excrete excess copper, indicating that half of the normal liver Atp7b copper
transporter activity is insufficient to deal with large copper intakes. Our results suggest that Wilson’s disease carriers
in the human population may be at increased risk of copper loading if chronically exposed to elevated copper in food or drinking
water. 相似文献
6.
The Ca2+ channel α1B subunit is a pore-forming component capable of generating N-type Ca2+ channel activity. Although the N-type Ca2+ channel plays a role in a variety of neuronal functions, α1B-deficient mice did not show apparent behavioral abnormality. In a previous study, we observed a compensatory increase of
mRNA expression of the P/Q-type Ca2+ channel α1A subunit gene in olfactory bulb of α1B-deficient mice with a CBA × C57BL/6 background; these mice showed a normal reproductive ability. In this study, we found
that the mRNA expression level of the α1A subunit was the same in olfactory bulb of wild, heterozygous, and homozygous α1B-deficient mice with a CBA/JN background, and the homozygous male mice produced no offspring. These results suggest that the
genetic background influences α1A subunit mRNA expression and reproductive ability in α1B-deficient mice. 相似文献
7.
8.
A 191-kb genomic fragment containing the human α-globin locus can rescue α-thalassemic mice 总被引:1,自引:0,他引:1
Keith Al-Hasani Jim Vadolas Anja S. Knaupp Hady Wardan Lucille Voullaire Robert Williamson Panayiotis A. Ioannou 《Mammalian genome》2005,16(11):847-853
A 191-kb human bacterial artificial chromosome (BAC) containing the human α-globin genomic locus was used to generate transgenic
mice that express, exclusively, human α-globin (huα-globin). Expression of huα-globin reaches a level of 36% of that of endogenous mouse α-globin (muα-globin) on a heterozygous mouse α-thalassemia background (muα-globin knockout, muα+/−). Hemizygous transgenic mice carrying the huα-globin locus on a heterozygous knockout background (huα+/0, muα++/−−) demonstrated complementation of most hematologic parameters. By crossing huα+/0, muα++/−− mice, we were able to generate mice entirely dependent on huα-globin synthesis. Breeding and fluorescent in situ hybridization studies demonstrate that only mice homozygous for the transgene were able to rescue embryonic lethal homozygous
muα-globin knockout embryos (muα−−/−−). Adult rescued mice produce hemoglobin at levels similar to wild-type mice, with partial red cell complementation based
on mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and red cell distribution width (RDW) measurements. Significant
erythrocythemia above wild-type levels seems to be the main compensatory mechanism for the normalization of the hemoglobin
levels in the rescued animals. Our studies demonstrate that the huα-globin locus in the 191-kb transgene contains all the necessary elements for the regulated expression of huα-globin in transgenic mice. This animal model should be valuable for studying the mechanisms regulating huα-globin production and for development of therapeutic strategies for β-thalassemia based on downregulation of α-globin expression.
We dedicate this article to the memory of our valued friend and colleague Panayiotis A. Ioannou who passed away during the
completion of this work 相似文献
9.
Bau DT Tsai MH Huang CY Lee CC Tseng HC Lo YL Tsai Y Tsai FJ 《The Chinese journal of physiology》2007,50(6):294-300
Inherited polymorphisms in DNA repair genes may be associated with differences in the repair capacity and contribute to individual's susceptibility to smoking-related cancers. Both XPA and XPD encode proteins that are part of the nucleotide excision repair (NER) pathway. In a hospital-based case-control study, we have investigated the influence of XPA A-23G and XPD Lys751Gln polymorphisms on oral cancer risk in a Taiwanese population. In total, 154 patients with oral cancer, and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. No significant association was found between the heterozygous variant allele (AG), the homozygous variant allele (AA) at XPA A-23G, the heterozygous variant allele (AC), the homozygous variant allele (CC) at XPD Lys751Gln, and oral cancer risk. There was no significant joint effect of XPA A-23G and XPD Lys751Gln on oral cancer risk either. Since XPA and XPD are both NER genes, which are very important in removing tobacco-induced DNA adducts, further stratified analyses of both genotype and smoking habit were performed. We found a synergistic effect of variant genotypes of both XPA and XPD, and smoking status on oral cancer risk. Our results suggest that the genetic polymorphisms are modified by environmental carcinogen exposure status, and combined analyses of both genotype and personal habit record are a better access to know the development of oral cancer and useful for primary prevention and early intervention. 相似文献
10.
The Ca(2+) channel alpha(1B) subunit is a pore-forming component capable of generating N-type Ca(2+) channel activity. Although the N-type Ca(2+) channel plays a role in a variety of neuronal functions, alpha(1B)-deficient mice with a CBA/JN genetic background show no apparent behavioral or anatomical-histological abnormality, presumably owing to compensation by other Ca(2+) channels. In this study, we examined the mRNA expression of the alpha(1A), alpha(1C), alpha(1D), alpha(1E), beta(1), beta(2), beta(3) and beta(4) subunits in the olfactory bulb, cerebral cortex, hippocampus and cerebellum of alpha(1B)-deficient mice. We found that the mRNA expression levels of the alpha(1A), alpha(1C), alpha(1D), alpha(1E), beta(1), beta(2), beta(3) and beta(4) subunits were the same in the olfactory bulbs of wild, heterozygous and homozygous alpha(1B)-deficient mice. In the cerebral cortex, alpha(1A) mRNA in homozygous alpha(1B)-deficient mice was expressed at a higher level than in wild or heterozygous mice, but no difference in the expression levels of the alpha(1C), alpha(1D), alpha(1E), beta(1), beta(2), beta(3) and beta(4) subunits was found among wild, heterozygous and homozygous mice. In hippocampus and cerebellum, beta(4) mRNA in homozygous alpha(1B)-deficient mice was expressed at a higher level than in wild or heterozygous mice, but no difference in the expression levels of the alpha(1A), alpha(1C), alpha(1D), alpha(1E), beta(1), beta(2) and beta(3) subunits was found among wild, heterozygous and homozygous mice. These results suggest that the compensatory mechanisms differ in different brain regions of alpha(1B)-deficient mice with a CBA/JN genetic background. 相似文献
11.
In recent years, there have been a large number of neuropeptides discovered that regulate food intake. Many of these peptides regulate food intake by increasing or decreasing nitric oxide (NO). In the current study, we compared the effect of the food modulators ghrelin, NPY and CCK in NOS KO mice. Satiated homozygous and heterozygous NOS KO mice and their wild type controls were administered ghrelin ICV. Food intake was measured for 2 h post injection. Ghrelin did not increase food intake in the homozygous NOS KO mice compared to vehicle treated NOS KO mice, whereas food intake was increased in the wild type controls compared to vehicle treated wild type controls. NPY was administered ICV and food intake measured for 2 h. Homozygous NOS KO mice showed no increase in food intake after NPY administration, whereas the wild type controls did. In our final study, we administered CCK intraperitoneally to homozygous and heterozygous NOS KO mice and their wild type controls after overnight food deprivation. Food intake was measured for 1 h after injection. CCK inhibited food intake in wild type mice after overnight food deprivation, however, CCK failed to inhibit food intake in the NOS KO mice. The heterozygous mice showed partial food inhibition after the CCK. The current results add further support to the theory that NO is a central mediator in food intake. 相似文献
12.
Friedberg EC Bond JP Burns DK Cheo DL Greenblatt MS Meira LB Nahari D Reis AM 《Mutation research》2000,459(2):99-108
Mice that are genetically engineered are becoming increasingly more powerful tools for understanding the molecular pathology of many human hereditary diseases, especially those that confer an increased predisposition to cancer. We have generated mouse strains defective in the Xpc gene, which is required for nucleotide excision repair (NER) of DNA. Homozygous mutant mice are highly prone to skin cancer following exposure to UVB radiation, and to liver and lung cancer following exposure to the chemical carcinogen acetylaminofluorene (AAF). Skin cancer predisposition is significantly augmented when mice are additionally defective in Trp53 (p53) gene function. We also present the results of studies with mice that are heterozygous mutant in the Apex (Hap1, Ref-1) gene required for base excision repair and with mice that are defective in the mismatch repair gene Msh2. Double and triple mutant mice mutated in multiple DNA repair genes have revealed several interesting overlapping roles of DNA repair pathways in the prevention of mutation and cancer. 相似文献
13.
Abstract The regulation of reproductive performance in small mammals may be determined by extrinsic or intrinsic parameters. In a large‐scale, replicated field experiment we monitored the seasonal fluctuation in food availability and tested the effects of food addition on the reproductive performance of wild house mice (Mus domesticus) in south‐eastern Australia. Ovulation rates and litter size increased during spring and peaked in October/November. Ovulation rate was consistently higher than litter size by approximately 1.2 embryos (19%). None of the extrinsic parameters measured (food quality and quantity, mouse abundance) had an impact on reproductive performance. The addition of food did not prevent the mid summer decrease in ovulation rates nor did it alter the difference between ovulation rates and litter size. While the number of previous pregnancies did not affect reproductive performance, the age of mice did: older mice tended to have higher ovulation rates than younger mice. The effect of age‐dependent changes in ovulation rates on population growth rates of house mice seemed to be of limited importance. We conclude that the reproductive output in wild house mice is determined by ovulation rates and not by litter size. The regulation of ovulation rates through an intrinsic factor (age) seems evident but the importance of food availability and house mouse abundance for ovulation rates is low. 相似文献
14.
15.
Eniko Nagy Ramona M. Rodriguiz William C. Wetsel Nancie J. MacIver Laura P. Hale 《PloS one》2016,11(4)
Studies in transgenic murine models have provided insight into the complexity underlying inflammatory bowel disease (IBD), a disease hypothesized to result from an injurious immune response against intestinal microbiota. We recently developed a mouse model of IBD that phenotypically and histologically resembles human childhood-onset ulcerative colitis (UC), using mice that are genetically modified to be deficient in the cytokines TNF and IL-10 (“T/I” mice). Here we report the effects of early life onset of colon inflammation on growth and reproductive performance of T/I mice. T/I dams with colitis often failed to get pregnant or had small litters with pups that failed to thrive. Production was optimized by breeding double homozygous mutant T/I males to females homozygous mutant for TNF deficiency and heterozygous for deficiency of IL-10 (“T/I-het” dams) that were not susceptible to spontaneous colon inflammation. When born to healthy (T/I-het) dams, T/I pups initially gained weight similarly to wild type (WT) pups and to their non-colitis-susceptible T/I-het littermates. However, their growth curves diverged between 8 and 13 weeks, when most T/I mice had developed moderate to severe colitis. The observed growth failure in T/I mice occurred despite a significant increase in their food consumption and in the absence of protein loss in the stool. This was not due to TNF-induced anorexia or altered food consumption due to elevated leptin levels. Metabolic studies demonstrated increased consumption of oxygen and water and increased production of heat and CO2 in T/I mice compared to their T/I-het littermates, without differences in motor activity. Based on the clinical similarities of this early life onset model of IBD in T/I mice to human IBD, these results suggest that mechanisms previously hypothesized to explain growth failure in children with IBD require re-evaluation. The T/I mouse model may be useful for further investigation of such mechanisms and for development of therapies to prevent reproductive complications and/or growth failure in humans with IBD. 相似文献
16.
Differential processing of UV mimetic and interstrand crosslink damage by XPF cell extracts 总被引:1,自引:1,他引:0
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We have recently developed a mammalian cell free assay in which interstrand crosslinks induce DNA synthesis in both damaged and undamaged plasmids co-incubated in the same extract. We have also shown using hamster mutants that both ERCC1 and XPF are required for the observed incorporation. Here, we show that extracts from an XPF patient cell line differentially process UV mimetic damage and interstrand crosslinks in vitro. XPF extracts are highly defective in the stimulation of repair synthesis by N-acetoxy-N- acetylaminofluorene, but are proficient in the stimulation of DNA synthesis by psoralen interstrand crosslinks. In addition, we show that extracts from the hamster UV140 mutant, which has high UV sensitivity, but moderate mitomycin C sensitivity, are similar in both assays to XPF cell extracts. These findings support the hypothesis that the activities of XPF in nucleotide excision repair (NER) and crosslink repair are separable, and that mutations in XPF patients result in the abolition of NER, but not recombinational repair pathways, which are likely to be essential as has been observed in ERCC1 homozygous –/– mice. 相似文献
17.
B cell development in mice that lack one or both immunoglobulin kappa light chain genes. 总被引:14,自引:5,他引:9
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J Chen M Trounstine C Kurahara F Young C C Kuo Y Xu J F Loring F W Alt D Huszar 《The EMBO journal》1993,12(3):821-830
We have generated mice that lack the ability to produce immunoglobulin (Ig) kappa light chains by targeted deletion of J kappa and C kappa gene segments and the intervening sequences in mouse embryonic stem cells. In wild type mice, approximately 95% of B cells express kappa light chains and only approximately 5% express lambda light chains. Mice heterozygous for the J kappa C kappa deletion have approximately 2-fold more lambda+ B cells than wild-type littermates. Compared with normal mice, homozygous mutants for the J kappa C kappa deletion have about half the number of B cells in both the newly generated and the peripheral B cell compartments, and all of these B cells express lambda light chains in their Ig. Therefore, homozygous mutant mice appear to produce lambda-expressing cells at nearly 10 times the rate observed in normal mice. These findings demonstrate that kappa gene assembly and/or expression is not a prerequisite for lambda gene assembly and expression. Furthermore, there is no detectable rearrangement of 3' kappa RS sequences in lambda+ B cells of the homozygous mutant mice, thus rearrangements of these sequences, per se, is not required for lambda light chain gene assembly. We discuss these findings in the context of their implications for the control of Ig light chain gene rearrangement and potential applications of the mutant animals. 相似文献
18.
Atmospheric changes could strongly influence how terrestrial ecosystems function by altering nutrient cycling. We examined
how the dynamics of nutrient release from leaf litter responded to two important atmospheric changes: rising atmospheric CO2 and tropospheric O3. We evaluated the independent and combined effects of these gases on foliar litter nutrient dynamics in aspen (Populus tremuloides Michx) and birch (Betula papyrifera Marsh)/aspen communities at the Aspen FACE Project in Rhinelander, WI. Naturally senesced leaf litter was incubated in litter
bags in the field for 735 days. Decomposing litter was sampled six times during incubation and was analyzed for carbon, and
both macro (N, P, K, S, Ca, and Mg) and micro (Mn, B, Zn and Cu) nutrient concentrations. Elevated CO2 significantly decreased the initial litter concentrations of N (−10.7%) and B (−14.4%), and increased the concentrations
of K (+23.7%) and P (+19.7%), with no change in the other elements. Elevated O3 significantly decreased the initial litter concentrations of P (−11.2%), S (−8.1%), Ca (−12.1%), and Zn (−19.5%), with no
change in the other elements. Pairing concentration data with litterfall data, we estimated that elevated CO2 significantly increased the fluxes to soil of all nutrients: N (+12.5%), P (+61.0%), K (+67.1%), S (+28.0%), and Mg (+40.7%),
Ca (+44.0%), Cu (+38.9%), Mn (+62.8%), and Zn (+33.1%). Elevated O3 had the opposite effect: N (−22.4%), P (−25.4%), K (−27.2%), S (−23.6%), Ca (−27.6%), Mg (−21.7%), B (−16.2%), Cu (−20.8%),
and Zn (−31.6%). The relative release rates of the nine elements during the incubation was: K ≥ P ≥ mass ≥ Mg ≥ B ≥ Ca ≥ S ≥ N ≥ Mn ≥ Cu ≥ Zn.
Atmospheric changes had little effect on nutrient release rates, except for decreasing Ca and B release under elevated CO2 and decreasing N and Ca release under elevated O3. We conclude that elevated CO2 and elevated O3 will alter nutrient cycling more through effects on litter production, rather than litter nutrient concentrations or release
rates. 相似文献
19.
20.
Kusumoto R Masutani C Sugasawa K Iwai S Araki M Uchida A Mizukoshi T Hanaoka F 《Mutation research》2001,485(3):219-227
The XPC-HR23B complex, a mammalian factor specifically involved in global genomic nucleotide excision repair (NER) has been shown to bind various forms of damaged DNA and initiate DNA repair in cell-free reactions. To characterize the binding specificity of this factor in more detail, a method based on immunoprecipitation was developed to assess the relative affinity of XPC-HR23B for defined lesions on DNA. Here we show that XPC-HR23B preferentially binds to UV-induced (6-4) photoproducts (6-4PPs) as well as to cholesterol, but not to the cyclobutane pyrimidine dimer (CPD), 8-oxoguanine (8-oxo-G), O6-methylguanine (O6-Me-G), or a single mismatch. Human whole cell extracts could efficiently excise 6-4PPs and cholesterol in an XPC-HR23B-dependent manner, but not 8-oxo-G, O6-Me-G or mismatches. Thus, there was good correlation between the binding specificity of XPC-HR23B for certain types of lesion and the ability of human cell extracts to excise these lesions, supporting the model that XPC-HR23B initiates global genomic NER. Although, XPC-HR23B does not preferentially bind to CPDs, the excision of CPDs in human whole cell extracts was found to be absolutely dependent on XPC-HR23B, in agreement with the in vivo observation that CPDs are not removed from the global genome in XP-C mutant cells. These results suggest that, in addition to the excision repair pathway initiated by XPC-HR23B, there exists another sub-pathway for the global genomic NER that still requires XPC-HR23B but is not initiated by XPC-HR23B. Possible mechanisms will be discussed. 相似文献