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Semin Cell Dev Biol,
2016]
During meiotic prophase, chromosomes pair and synapse with their homologs and undergo programmed DNA double-strand break (DSB) formation to initiate meiotic recombination. These DSBs are processed to generate a limited number of crossover recombination products on each chromosome, which are essential to ensure faithful segregation of homologous chromosomes. The nematode Caenorhabditis elegans has served as an excellent model organism to investigate the mechanisms that drive and coordinate these chromosome dynamics during meiosis. Here we focus on our current understanding of the regulation of DSB induction in C. elegans. We also review evidence that feedback regulation of crossover formation prolongs the early stages of meiotic prophase, and discuss evidence that this can alter the recombination pattern, most likely by shifting the genome-wide distribution of DSBs.
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Ecotoxicol Environ Saf,
2015]
As emerging pollutants, antibiotic sulfonamides are continuously emitted into the environment and encounter those already-existing contaminants, e.g., heavy metals, which may cause toxicity interactions in polluted habitats. So far, the sulfonamide mixture effects and the combinational effects between sulfonamides and metals have been seldom studied. In this study, lifespan, lethality (24 and 120 h), locomotion behavior and growth (96 h) of Caenorhabditis elegans were measured after exposure to mixtures containing sulfonamides (sulfadiazine, sulfapyridine, sulfamethoxazole and sulfamethazine as representatives) and/or metals (cadmium, copper, lead and zinc as representatives) at environmental concentrations. Results showed that sulfonamides did not cause acute (24 h) lethality at chosen concentrations, but they decreased the lifespan in a concentration dependent fashion. Moreover, sulfonamide mixtures caused synergisms at higher concentrations but antagonisms at lower concentrations on the subacute (120 h) lethal effects. The toxicity interactions of sulfonamide mixtures were addition action on body bending frequency, and antagonism on reversal movement and body length. In sulfonamide and metal mixtures, the toxicity interactions were different in acute and subacute lethal results, indicating the influence of the exposure time. According to the comparison among effects of mixtures containing sulfonamides and/or metals, subacute lethality of sulfonamides was enhanced by metals based on the synergistic mixture effects, while their inhibitions on the growth and behavior were weakened by metals based on the antagonistic mixture effects. Our findings highlighted studies on combinational effects between emerging and common contaminants for more accurate environmental risk evaluation, and also urged further mechanism studies.
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Nat Struct Mol Biol,
2023]
Cohesins are ancient and ubiquitous regulators of chromosome architecture and function, but their diverse roles and regulation remain poorly understood. During meiosis, chromosomes are reorganized as linear arrays of chromatin loops around a cohesin axis. This unique organization underlies homolog pairing, synapsis, double-stranded break induction, and recombination. We report that axis assembly in Caenorhabditis elegans is promoted by DNA-damage response (DDR) kinases that are activated at meiotic entry, even in the absence of DNA breaks. Downregulation of the cohesin-destabilizing factor WAPL-1 by ATM-1 promotes axis association of cohesins containing the meiotic kleisins COH-3 and COH-4. ECO-1 and PDS-5 also contribute to stabilizing axis-associated meiotic cohesins. Further, our data suggest that cohesin-enriched domains that promote DNA repair in mammalian cells also depend on WAPL inhibition by ATM. Thus, DDR and Wapl seem to play conserved roles in cohesin regulation in meiotic prophase and proliferating cells.
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PLoS One,
2016]
Earlier studies showed that toxicities of excessive metals lasted over generations. Yet, these studies mainly employed one-generation exposure, and the effects of multigenerational challenges need further studies. Presently, Caenorhabditis elegans were exposed to cadmium, copper, lead and zinc for four consecutive generations (G1 to G4) at environmental concentrations. The feeding, growth, initial reproduction, superoxide dismutase (SOD) and catalase (CAT) were determined. All data were represented in the percentage of that in control (POC), and POC in the control was normalized to 100%. In G1 and G2, the POC values in feeding, growth and initial reproduction were generally within 10% of the control (100%), indicating non-significant effects. The POC values in SOD and CAT were significantly higher than 100%, showing stimulatory effects. In G3 and G4, the POC values in feeding, growth and initial reproduction were significantly lower than 100%, showing inhibitory effects which were more severe in G4 than in G3. Meanwhile, SOD and CAT continuously showed stimulatory effects, and the stimulatory effects on SOD increased from G1 to G4. The effects with multigenerational challenges were different from those in one-generation exposure. The effects in later generations demonstrated the importance of multigenerational challenges in judging long-term influences of metals.
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Ecotoxicol Environ Saf,
2016]
Trans-generational effects are increasingly used to indicate long-term influences of environmental pollutants. However, such studies can be complex and yield inconclusive results. In this study, the trans-generational effects of sulfamethoxazole (SMX) on Caenorhabditis elegans on lifespan, reproduction and population growth were tested for 7 consecutive generations, which included gestating generation (F0), embryo-exposed generation (F1), germline-exposed generation (F2), the first non-exposed generation (F3) and the three following generations (F4-F6). Results showed that lifespan was significantly affected by embryo exposure (F1) at 400m SMX with a value as low as 47% of the control. The reproduction (a total brood size as 49% of the control) and population growth (81% of the control) were significantly affected in germline exposure (F2). Lifespan and reproduction were severely inhibited in non-exposed generations, confirming the real trans-generational effects. Notably, initial reproduction and reproduction duration showed opposite generation-related changes, indicating their interplay in the overall brood size. The population growth rate was well correlated with median lethal time, brood size and initial reproduction, which indicated that the population would increase when the nematodes lived longer and reproduced more offspring within shorter duration.
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Org Lett,
2011]
Lymphatic filariasis is caused by the parasitic nematodes Brugia malayi and Wuchereria bancrofti, and asparaginyl-tRNA synthetase (AsnRS) is considered an excellent antifilarial target. The discovery of three new tirandamycins (TAMs), TAM E (1), F (2), and G (3), along with TAM A (4) and B (5), from Streptomyces sp. 17944 was reported. Remarkably, 5 selectively inhibits the B. malayi AsnRS and efficiently kills the adult B. malayi parasite, representing a new lead scaffold to discover and develop antifilarial drugs.
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Org Lett,
2012]
Lymphatic filariasis is caused by the Brugia malayi parasite. Three new congeners of the depsipeptide WS9326A (1), WS9326C (2), WS9326D (3), and WS9326E (4), were isolated from Streptomyces sp. 9078 by using a B. malayi asparaginyl-tRNA synthetase (BmAsnRS) inhibition assay. WS9326D specifically inhibits the BmAsnRS, kills the adult B. malayi parasite, and does not exhibit significant general cytotoxicity to human hepatic cells, representing a new lead scaffold for antifilarial drug discovery.
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J Hazard Mater,
2013]
Sulfonamides are one typical antibiotic which is an emerging hazardous material to the ecological stability due to their continuously application and biological effects to non-target organisms. The parent-progeny transgenerational effects need investigations to indicate their long-term consequences. Currently, we tested the transgenerational effects of sulfadiazine (SD), sulfapyridine (SP) and sulfamethazine (SMZ) on L3 larva of Caenorhabditis elegans. The nematodes were exposed to aqueous sulfonamides at micromolar concentrations for 96 h, and then the effects on the behavior and growth in the exposed parent and unexposed progeny were measured. Results showed that SD, SP and SMZ inhibited three behavior indicators including body bending frequency (BBF), reversal movement (RM) and Omega turn (OT), and the growth indicator (body length, BL). Behavior indicators showed higher sensitivities than the growth indicator, and BBF had the highest sensitivity among the behavior indicators. Moreover, the effects of sulfonamides were also observed in the unexposed progeny with partially rescued or more severe inhibitions on the indicators. The behavior also showed higher sensitivity than the growth in the progeny. The transgenerational effects of sulfonamides indicated that parental exposure can multiply the harmful effects of antibiotic pollution in following generations and their potential ecological risks at environmental concentrations were further raised.
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International Worm Meeting,
2017]
The DNA Damage Response (DDR), which is orchestrated by evolutionarily conserved PI3K family kinases ATM and ATR (ATM-1 and ATL-1 in C. elegans), safeguards genome integrity during a variety of developmental processes. Studies in many organisms have revealed central roles for DDR kinases in meiosis, but the roles of ATM-1 and ATL-1 are not well-defined in C. elegans meiosis. Efforts to characterize ATM/ATR function have been complicated by the essential roles of ATL-1 during cell proliferation, including in the premeiotic germline. To circumvent these issues to enable investigation of the roles of ATM/ATR during meiosis, we generated alleles of ATM-1 and ATL-1 that can be depleted using the auxin-inducible degradation (AID) system. Depletion of ATM-1, ATL-1, and both kinases together, indicates that these kinases have strongly overlapping meiotic functions. We find that signaling by ATM/ATR is strongly induced during early meiosis and declines at mid-prophase. While this coincides with activation and inactivation of the meiosis-specific CHK-2 kinase, we find that CHK-2 is activated independently of ATM/ATR activity. Conversely, CHK-2 does not appear to activate ATM/ATR, although they are induced in response to meiotic double-strand breaks (DSBs), which do require CHK-2. Codepletion of ATM-1 and ATL-1 causes a severe defect in meiotic cohesion; COH-3/4-containing cohesin complexes are strongly reduced along meiotic chromosomes and REC-8 is not detected, HORMA-domain proteins fail to be recruited to the axes, and synapsis is therefore abrogated. We further identified WAPL-1, a negative regulator of cohesion, as a downstream effectors of the meiotic DDR pathway. Co-depletion of ATM-1/ATL-1 or CHK-2 results in mislocalization of WAPL-1 throughout the germline. Through our ongoing analysis, we plan to systematically define the targets of ATM/ATR signaling in C. elegans and to investigate how these kinases contribute to germline maintenance, fertility, and genome integrity.
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Chemosphere,
2018]
Adverse effects of sulfonamide antibiotics (SAs) include growth inhibition and antioxidant activation which showed trade-off effects. Yet, the influence of food availability on such effects have not been thoroughly investigated. Caenorhabditis elegans were exposed to four SAs at high and low food availabilities which were represented by the optical densities of bacteria at 600nm. The nematode feeding, growth and antioxidants including superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) were determined. Results showed that the control nematodes at low food availability had less growth and greater antioxidant responses than the nematodes at high food availability. In SA exposure, the nematode growth in the presence of food (at both high and low food availability) was less than that in its absence, supporting the role of food as an exposure pathway. The nematode growth at low food availability showed significantly greater inhibition than at high food availability (p<0.05). The nematode antioxidants showed stimulations, and CAT had the greatest stimulation. Moreover, the stimulation on CAT at low food availability were significantly higher than those at high food availability (p<0.05). That is to say, SA exposure at low food availability further biased the trade-off effects towards more energy investment in antioxidant with less in growth. Further studies on the expression levels of CAT encoding genes demonstrated that cells in intestines were the main antioxidant response sites, which further supported the contributions of food to the observed toxicities.