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101.
Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair 总被引:1,自引:0,他引:1
Williams RS Moncalian G Williams JS Yamada Y Limbo O Shin DS Groocock LM Cahill D Hitomi C Guenther G Moiani D Carney JP Russell P Tainer JA 《Cell》2008,135(1):97-109
Mre11 forms the core of the multifunctional Mre11-Rad50-Nbs1 (MRN) complex that detects DNA double-strand breaks (DSBs), activates the ATM checkpoint kinase, and initiates homologous recombination (HR) repair of DSBs. To define the roles of Mre11 in both DNA bridging and nucleolytic processing during initiation of DSB repair, we combined small-angle X-ray scattering (SAXS) and crystal structures of Pyrococcus furiosus Mre11 dimers bound to DNA with mutational analyses of fission yeast Mre11. The Mre11 dimer adopts a four-lobed U-shaped structure that is critical for proper MRN complex assembly and for binding and aligning DNA ends. Further, mutations blocking Mre11 endonuclease activity impair cell survival after DSB induction without compromising MRN complex assembly or Mre11-dependant recruitment of Ctp1, an HR factor, to DSBs. These results show how Mre11 dimerization and nuclease activities initiate repair of DSBs and collapsed replication forks, as well as provide a molecular foundation for understanding cancer-causing Mre11 mutations in ataxia telangiectasia-like disorder (ATLD). 相似文献
102.
Linking human health risk to environmental factors can be a challenge for clinicians, public health departments, and environmental
health researchers. While it is possible that nonhuman animal species could help identify and mitigate such linkages, the
fields of animal and human health remain far apart, and the prevailing human health attitude toward disease events in animals
is an “us vs. them” paradigm that considers the degree of threat that animals themselves pose to humans. An alternative would
be the development of the concepts of animals as models for environmentally induced disease, as well as potential “sentinels”
providing early warning of both noninfectious and infectious hazards in the environment. For such concepts to truly develop,
critical knowledge gaps need to be addressed using a “shared risk” paradigm based on the comparative biology of environment–host
interactions in different species. 相似文献
103.
Sneddon AA Tsofliou F Fyfe CL Matheson I Jackson DM Horgan G Winzell MS Wahle KW Ahren B Williams LM 《Obesity (Silver Spring, Md.)》2008,16(5):1019-1024
This study aimed to determine the effect of supplementation with conjugated linoleic acids (CLAs) plus n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) on body composition, adiposity, and hormone levels in young and older, lean and obese men. Young (31.4+/-3.9 years) lean (BMI, 23.6+/-1.5 kg/m2; n=13) and obese (BMI, 32.4+/-1.9 kg/m2; n=12) and older (56.5+/-4.6 years) lean (BMI, 23.6+/-1.5 kg/m2; n=20) and obese (BMI, 32.0+/-1.6 kg/m2; n=14) men participated in a double-blind placebo-controlled, randomized crossover study. Subjects received either 6 g/day control fat or 3 g/day CLA (50:50 cis-9, trans-11:trans-10, cis-12) and 3 g/day n-3 LC-PUFA for 12 weeks with a 12-week wash-out period between crossovers. Body composition was assessed by dual-energy X-ray absorptiometry. Fasting adiponectin, leptin, glucose, and insulin concentrations were measured and insulin resistance estimated by homeostasis model assessment for insulin resistance (HOMA-IR). In the younger obese subjects, CLA plus n-3 LC-PUFA supplementation compared with control fat did not result in increased abdominal fat and raised both fat-free mass (2.4%) and adiponectin levels (12%). CLA plus n-3 LC-PUFA showed no significant effects on HOMA-IR in any group but did increase fasting glucose in older obese subjects. In summary, supplementation with CLA plus n-3 LC-PUFA prevents increased abdominal fat mass and raises fat-free mass and adiponectin levels in younger obese individuals without deleteriously affecting insulin sensitivity, whereas these parameters in young and older lean and older obese individuals were unaffected, apart from increased fasting glucose in older obese men. 相似文献
104.
Foulds LM Boysen RI Crane M Yang Y Muir JA Smith AI de Kretser DM Hearn MT Hedger MP 《Biology of reproduction》2008,79(3):525-536
The ability of the gametes to escape detection by the immune system is vital to successful human reproduction. Furthermore, the observed capacity of the testis in some species to support tissue grafts without rejection (immunological privilege) indicates that spermatogenic cells are protected by local immunoregulatory mechanisms. One of these mechanisms involves targeting T cells for inactivation and destruction within the testicular environment. Although the fluids of the testis and ovary surrounding the developing gametes contain soluble factors that inhibit T cells, the identity of the molecule(s) responsible for this activity has been unknown. Using a specific T-cell proliferation assay to monitor bioactivity, these molecules were purified from bovine ovarian follicular fluid by methanol extraction and sequential reverse-phase HPLC (RP-HPLC). All purified active fractions coincided with the elution position on RP-HPLC of several small molecules ranging in size from 496 to 522 Da. The same molecules were localized to the immunosuppressive fractions of rat testicular interstitial fluid. The active molecules were identified, using capillary electrophoresis electrospray ionization mass spectroscopy, as lyso-glycerophosphocholines (lyso-GPCs), namely, 1-palmitoyl-sn-glycero-3-phosphocholine, 1-oleoyl-sn-glycero-3-phosphocholine, a 18:2a/lyso-GPC (putatively, 1-linoleoyl-sn-glycero-3-phosphocholine), and a 20:4a/lyso-GPC (putatively, 1-arachidonyl-sn-glycero-3-phosphocholine). Comparison of the bioactivity and mass spectroscopy profiles of two of the purified molecules with their synthetic standards confirmed the identification. These molecules inhibit T-cell proliferation in response to activation and induce apoptosis of these cells in a time- and dose-dependent manner. The emergence of gonadal lyso-GPCs as potential regulators of critical immune events opens up new avenues of inquiry into the origins of autoimmune infertility and more generally into mechanisms of peripheral immunoregulation and the development of novel immunosuppressives. 相似文献
105.
Telomere Dysfunction Triggers Developmentally Regulated Germ Cell
Apoptosis 总被引:10,自引:0,他引:10
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Michael T. Hemann Karl Lenhard Rudolph Margaret A. Strong Ronald A. DePinho Lynda Chin Carol W. Greider 《Molecular biology of the cell》2001,12(7):2023-2030
Telomere dysfunction results in fertility defects in a number of organisms. Although data from fission yeast and Caenorhabditis elegans suggests that telomere dysfunction manifests itself primarily as defects in proper meiotic chromosome segregation, it is unclear how mammalian telomere dysfunction results in germ cell death. To investigate the specific effects of telomere dysfunction on mammalian germ cell development, we examined the meiotic progression and germ cell apoptosis in late generation telomerase null mice. Our results indicate that chromosome asynapsis and missegregation are not the cause of infertility in mice with shortened telomeres. Rather, telomere dysfunction is recognized at the onset of meiosis, and cells with telomeric defects are removed from the germ cell precursor pool. This germ cell telomere surveillance may be an important mechanism to protect against the transmission of dysfunctional telomeres and chromosomal abnormalities. 相似文献
106.
First Nuclear DNA C-values for Another 25 Angiosperm Families 总被引:5,自引:5,他引:0
Hanson Lynda; M C Mahon Kathryn A.; Johnson Margaret A. T.; Bennett Michael D. 《Annals of botany》2001,88(5):851-858
Nuclear DNA C-value is an important genomic biodiversity characterwith many uses. An international workshop sponsored by Annalsof Botany and held at the Royal Botanic Gardens, Kew, UK, in1997 identified major gaps in our knowledge of plant DNA C-valuesand recommended targets for new work. Improved taxonomic coveragewas highlighted as a key need for angiosperms, especially atthe familial level. In 1997 C-values were known for only approx.32% of angiosperm families; a goal of complete familial representationby 2002 was recommended. A review published in 2000 (Bennettet al.;Annals of Botany86: 859909) noted poor progresstowards this aim: of the 691 first C-values for species only12 (1.7%) were for unrepresented families. We began new workto address this in 1999, reporting first DNA C-values for 25angiosperm families in 2001 (Hanson et al.;Annals of Botany87:251258). Here we report first DNA C-values for a further25 angiosperm families, increasing familial coverage in angiospermsto approx. 45%. Such targeting remains essential to approachthe goal set by the 1997 workshop of familial coverage for angiospermswithin 5 years. The 4C DNA amounts presented here range from0.76 pg (similar toArabidopsis thaliana ) in Roridula gorgonias(Roridulaceae)to 29.74 pg in Gunnera manicata(Gunneraceae). 1C values were< 3.5 pg in 23 of the 25 families; these data provide furthersupport for the view that ancestral angiosperms almost certainlyhad small genomes (defined as 1C 相似文献
107.
Mass spectrometric study of the Escherichia coli repressor proteins, IcIR and GcIR, and their complexes with DNA
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Lynda J. Donald David J. Hosfield Susan L. Cuvelier Werner Ens Kenneth G. Standing Harry W. Duckworth 《Protein science : a publication of the Protein Society》2001,10(7):1370-1380
In Escherichia coli, the IclR protein regulates both the aceBAK operon and its own synthesis. Database homology searches have identified many IclR-like proteins, now known as the IclR family, which can be identified by a conserved C-terminal region. We have cloned and purified one of these proteins, which we have named GclR (glyoxylate carboligase repressor). Although purification is straightforward, both the IclR and GclR proteins are difficult to manipulate, requiring high salt (up to 0.6 M KCl) for solubility. With the advent of nanospray ionization, we could transfer the proteins into much higher concentrations of volatile buffer than had been practical with ordinary electrospray. In 0.5 M ammonium bicarbonate buffer, both proteins were stable as tetramers, with a small amount of dimer. In a separate experiment, we found that IclR protein selected from a random pool a sequence which matched exactly that of the presumed binding region of the GclR protein, although IclR does not regulate the gcl gene. We designed a 29 bp synthetic DNA to which IclR and GclR bind, and with which we were able to form noncovalent DNA-protein complexes for further mass spectrometry analysis. These complexes were far more stable than the proteins alone, and we have evidence of a stoichiometry which has not been described previously with (protein monomer : dsDNA) = (4 : 1). 相似文献
108.
Lynda D. Corkum 《Hydrobiologia》1992,239(2):101-114
This study was designed to test the biome dependency hypothesis, which predicts that similar assemblages of macroinvertebrates occur along rivers both within and among drainage basins if the basins occupy the same biome. Benthic macroinvertebrates were collected from three drainage basins within each of three biomes in Canada, the eastern deciduous forests (EDF) of southwestern Ontario, the grasslands of south-central Alberta, and the montane coniferous forests (MCF) of southeastern British Columbia. A total of 225 benthic samples (3 biomes × 3 rivers/biome × 5 sites/river × 5 samples/site) was collected in spring using a cylinder sampler.The significant interaction effect between biome and a site's location along a river indicated that spatial patterns of variation in total density and taxonomic composition were not spatially consistent among sites along rivers or among biomes. Total macroinvertebrate densities were equivalent between the EDF and grassland sites. However, total density was substantially lower at the MCF sites than at sites in the other two biomes. The greatest differences in taxonomic composition occurred among biomes, although significant differences also occurred for all other sources of variation examined. Macroinvertebrate composition was more strongly associated with local, site-specific factors (riparian vegetation and land use) than with longitudinal gradients. Distinct site-specific taxonomic assemblages were evident in EDF, but not in the other two biomes where land use was more homogeneous. 相似文献
109.
Neil A. Littlefield Bruce S. Hass Lynda J. McGarrity Suzanne M. Morris 《Cell biology and toxicology》1991,7(3):203-214
The effects of magnesium (Mg) restriction on cell growth and the cell cycle were determined in transformed (TRL-8) and non-transformed (TRL-12-15) epithelial-like rat liver cells. Cells were cultured in RPMI 1640 medium in which the Mg concentration was reduced to 0.5, 0.1, and 0 × the concentration in the regular RPMI 1640 media (100mg/l). Cell growth in the transformed cells was not influenced by the Mg restriction as greatly as in the non-transformed cell line. Transit through the cell cycle also exhibited an independence of the Mg in the medium in the transformed cells. When transformed cells were grown for two generations in Mg-limited medium, the growth rate slowed to a rate similar to that demonstrated by the non-transformed cells. Analysis by flow cytometry showed that transit through the cell cycle was minimally slowed in Mg deficient transformed cells; however, transit through the G1 and S phases in the non-transformed cells was slowed. The TRL-8 cells in Mg-limited medium resulted in fewer nuclei in G1 with subsequent increases in the percentages of S-phase nuclei. The TRL 12-15 cells reacted oppositely with the number of G1 nuclei increased and the number of S-phase nuclei decreased. In respect to growth, these results show that epithelial cells respond in a similar manner to Mg-limitation as do fibroblast cells. The transformed cells exhibited a level of independence from Mg in respect to growth, reproduction, and cell-cycle kinetics. 相似文献
110.