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Drug and Chemical Toxicology Nov 2023Two different drug groups, typical (classic) and atypical (new), are used in the treatment of schizophrenia. Aripiprazole, an atypical antipsychotic chemical, is the...
Two different drug groups, typical (classic) and atypical (new), are used in the treatment of schizophrenia. Aripiprazole, an atypical antipsychotic chemical, is the active ingredient of the drug Abilify. This study was conducted to determine the possible genotoxic effect of aripiprazole. For this purpose, four different doses of aripiprazole (5; 10; 20, and 40 µg/mL) were examined with Chromosome Abnormality (CA), Sister Chromatid Exchange (SCE), Micronucleus (MN) tests. Based on these tests, Proliferation Index (PI), Percent Abnormal Cells (AC), Mitotic Index (MI), Micronuclear Binuclear Cell (MNBN), and Nuclear Division Index (NDI) levels were determined in human peripheral lymphocytes treated for 24 and 48 hours. Also, to determine possible binding sites of Aripiprazole on B-DNA molecular docking analysis was performed using AutoDock 4.0 (B-DNA dodecamer, PDB code: 1BNA). Aripiprazole binds to B-DNA with a very significant free binding energy (-11.88 Kcal/mol). According to our study, aripiprazole did not significantly change SCE, CA, AC percentage, MN frequencies when compared with control. According to these results, aripiprazole does not have a genotoxic effect. At the same time, no significant change was observed in the PI, MI, and NDI frequencies when compared with the control. In line with these results, it was observed that the use of aripiprazole in the treatment of schizophrenia did not pose any acute genotoxic and cytotoxic risk.
Topics: Humans; Aripiprazole; Molecular Docking Simulation; DNA, B-Form; Cells, Cultured; Micronucleus Tests; Sister Chromatid Exchange; Chromosome Aberrations; Lymphocytes; Mitotic Index; Mutagens
PubMed: 36278274
DOI: 10.1080/01480545.2022.2135008 -
Genes, Chromosomes & Cancer Aug 2023The majority of neurotrophic tyrosine receptor kinase (NTRK) rearranged neoplasms occur either in the superficial or deep soft tissues of extremities or trunk....
The majority of neurotrophic tyrosine receptor kinase (NTRK) rearranged neoplasms occur either in the superficial or deep soft tissues of extremities or trunk. Occasionally, it arises in visceral organs. However, its occurrence as a primary osseous tumor has not been documented thus far. Herein, we describe a unique case of an NTRK rearranged neoplasm that presented as a primary bony lesion. The tumor occurred in a 21-year-old woman who presented with an increasing pain in the right lower extremity. Radiologic examinations revealed a destructive lytic lesion located in the lower portion of the right femur. Histologically, the tumor was composed of haphazard fascicles of monomorphic spindle cells displaying mild nuclear atypia and rare mitotic activity. Immunohistochemically, the tumor cells showed focal staining of pan-TRK and S100 protein. Fluorescence in situ hybridization analysis was performed with the utilization of break-apart probes for NTRK1/NTRK2/NTRK3 genes. An NTRK3 rearrangement was identified. Subsequent next-generation sequencing (RNA-seq) revealed HMBOX1exon6::NTRK3exon 14 fusion. Our study illustrates, albeit extremely rare, that NTRK-rearranged neoplasms can arise as a primary bone lesion. In addition, we describe a novel HMBOX1::NTRK3 fusion that has not been documented before.
Topics: Female; Humans; Young Adult; Biomarkers, Tumor; Bone Neoplasms; Gene Fusion; Gene Rearrangement; Homeodomain Proteins; In Situ Hybridization, Fluorescence; Neoplasms, Connective and Soft Tissue; Oncogene Proteins, Fusion; Receptor Protein-Tyrosine Kinases; Receptor, trkA
PubMed: 36740981
DOI: 10.1002/gcc.23132 -
Journal of Cutaneous Pathology May 2024Calcified chondroid mesenchymal neoplasm is a recently recognized bone and soft tissue entity primarily found in the extremities and the temporomandibular joint. This... (Review)
Review
Calcified chondroid mesenchymal neoplasm is a recently recognized bone and soft tissue entity primarily found in the extremities and the temporomandibular joint. This neoplasm is typically driven by the fusion of the FN1 gene with a kinase. In this case report, we provide a detailed account of a rare superficial calcified chondroid mesenchymal neoplasm located on the left big toe, characterized by an FN1::FGFR2 fusion. The tumor exhibited a peripheral collarette and consisted of large intradermal histiocytoid to epithelioid cells with no mitotic activity. These cells displayed fine chromatin and abundant pale eosinophilic cytoplasm, forming a swirling syncytium. They were interspersed with localized areas of glassy chondromyxoid matrix containing randomly mineralized calcific material and isolated osteoclast-like giant cells. RNA sequencing confirmed the presence of an FN1 (exon 29)::FGFR2 (exon 7) gene fusion. Our report emphasizes the importance for dermatopathologists to consider this entity when evaluating superficial lesions displaying mesenchymal, chondroid, and calcified attributes.
Topics: Humans; Epithelioid Cells; Exons; Gene Fusion; Giant Cells; Receptor, Fibroblast Growth Factor, Type 2; Soft Tissue Neoplasms
PubMed: 38328983
DOI: 10.1111/cup.14593 -
Genes To Cells : Devoted To Molecular &... Jan 2024The mitotic cohesin complex necessary for sister chromatid cohesion and chromatin loop formation shows local and global association to chromosomes in response to DNA...
The mitotic cohesin complex necessary for sister chromatid cohesion and chromatin loop formation shows local and global association to chromosomes in response to DNA double-strand breaks (DSBs). Here, by genome-wide binding analysis of the meiotic cohesin with Rec8, we found that the Rec8-localization profile along chromosomes is altered from middle to late meiotic prophase I with cleavage-independent dissociation. Each Rec8-binding site on the chromosome axis follows a unique alternation pattern with dissociation and probably association. Centromeres showed altered Rec8 binding in late prophase I relative to mid-prophase I, implying chromosome remodeling of the regions. Rec8 dissociation ratio per chromosome is correlated well with meiotic DSB density. Indeed, the spo11 mutant deficient in meiotic DSB formation did not change the distribution of Rec8 along chromosomes in late meiotic prophase I. These suggest the presence of a meiosis-specific regulatory pathway for the global binding of Rec8-cohesin in response to DSBs.
Topics: Cell Cycle Proteins; Cohesins; DNA; DNA Breaks, Double-Stranded; Meiosis; Saccharomyces cerevisiae
PubMed: 37968127
DOI: 10.1111/gtc.13081 -
International Journal of Molecular... Oct 2023Rev7 is a regulatory protein with roles in translesion synthesis (TLS), double strand break (DSB) repair, replication fork protection, and cell cycle regulation. Rev7...
Rev7 is a regulatory protein with roles in translesion synthesis (TLS), double strand break (DSB) repair, replication fork protection, and cell cycle regulation. Rev7 forms a homodimer in vitro using its HORMA (Hop, Rev7, Mad2) domain; however, the functional importance of Rev7 dimerization has been incompletely understood. We analyzed the functional properties of cells expressing either wild-type mouse Rev7 or Rev7, a mutant that cannot dimerize. The expression of wild-type Rev7, but not the mutant, rescued the sensitivity of Rev7 cells to X-rays and several alkylating agents and reversed the olaparib resistance phenotype of Rev7 cells. Using a novel fluorescent host-cell reactivation assay, we found that Rev7 is unable to promote gap-filling TLS opposite an abasic site analog. The Rev7 dimerization interface is also required for shieldin function, as both Rev7 cells and Rev7 cells expressing Rev7 exhibit decreased proficiency in rejoining some types of double strand breaks, as well as increased homologous recombination. Interestingly, Rev7 retains some function in cell cycle regulation, as it maintains an interaction with Ras-related nuclear protein (Ran) and partially rescues the formation of micronuclei. The mutant Rev7 also rescues the G2/M accumulation observed in Rev7 cells but does not affect progression through mitosis following nocodazole release. We conclude that while Rev7 dimerization is required for its roles in TLS, DSB repair, and regulation of the anaphase promoting complex, dimerization is at least partially dispensable for promoting mitotic spindle assembly through its interaction with Ran.
Topics: Animals; Mice; Anaphase-Promoting Complex-Cyclosome; DNA Repair; DNA Replication; Mad2 Proteins; Mitosis
PubMed: 37958783
DOI: 10.3390/ijms242115799 -
BioRxiv : the Preprint Server For... Apr 2024The conserved Rad2/XPG family 5'-3' exonuclease, Exonuclease 1 (Exo1), plays many roles in DNA metabolism including during resolution of DNA double strand breaks (DSBs)...
UNLABELLED
The conserved Rad2/XPG family 5'-3' exonuclease, Exonuclease 1 (Exo1), plays many roles in DNA metabolism including during resolution of DNA double strand breaks (DSBs) via homologous recombination. Prior studies provided evidence that the end-resection activity of Exo1 is downregulated in yeast and mammals by Cdk1/2 family cyclin-dependent and checkpoint kinases, including budding yeast kinase Rad53 which functions in mitotic cells. Here we provide evidence that the master meiotic kinase Mek1, a paralogue of Rad53, limits 5'-3' single strand resection at the sites of programmed meiotic DNA breaks. Mutational analysis suggests that the mechanism of Exo1 suppression by Mek1 differs from that of Rad53.
ARTICLE SUMMARY
Meiotic recombination involves formation of programmed DNA double strand breaks followed by 5' to 3' single strand specific resection by nucleases including Exo1. We find that the activity of budding yeast Exo1 is downregulated during meiotic recombination by the master meiotic kinase Mek1. The mechanism of downregulation of Exo1 by Mek1 in meiosis does not depend on the same phospho-sites as those used by the mitotic kinase Rad53, a relative of Mek1 that downregulates Exo1 in mitosis.
PubMed: 38645032
DOI: 10.1101/2024.04.12.589255 -
Frontiers in Plant Science 2023A major challenge for plants in a rapidly changing climate is to adapt to rising temperatures. Some plants adapt to temperature conditions by generating an epigenetic...
A major challenge for plants in a rapidly changing climate is to adapt to rising temperatures. Some plants adapt to temperature conditions by generating an epigenetic memory that can be transmitted both meiotically and mitotically. Such epigenetic memories may increase phenotypic variation to global warming and provide time for adaptation to occur through classical genetic selection. The goal of this study was to understand how warmer temperature conditions experienced during sexual and asexual reproduction affect the transcriptomes of different strawberry () ecotypes. We let four European ecotypes reproduce at two contrasting temperatures (18 and 28°C), either asexually through stolon formation for several generations, or sexually by seeds (achenes). We then analyzed the transcriptome of unfolding leaves, with emphasis on differential expression of genes belonging to the epigenetic machinery. For asexually reproduced plants we found a general transcriptomic response to temperature conditions but for sexually reproduced plants we found less significant responses. We predicted several splicing isoforms for important genes (e.g. a SOC1, LHY, and SVP homolog), and found significantly more differentially presented splicing event variants following asexual vs. sexual reproduction. This difference could be due to the stochastic character of recombination during meiosis or to differential creation or erasure of epigenetic marks during embryogenesis and seed development. Strikingly, very few differentially expressed genes were shared between ecotypes, perhaps because ecotypes differ greatly both genetically and epigenetically. Genes related to the epigenetic machinery were predominantly upregulated at 28°C during asexual reproduction but downregulated after sexual reproduction, indicating that temperature-induced change affects the epigenetic machinery differently during the two types of reproduction.
PubMed: 37521931
DOI: 10.3389/fpls.2023.1213311 -
BioRxiv : the Preprint Server For... Apr 202453BP1 plays a crucial role in regulating DNA damage repair pathway choice and checkpoint signaling in somatic cells; however, its role in meiosis has remained enigmatic....
53BP1 plays a crucial role in regulating DNA damage repair pathway choice and checkpoint signaling in somatic cells; however, its role in meiosis has remained enigmatic. In this study, we demonstrate that the ortholog of 53BP1, HSR-9, associates with chromatin in both proliferating and meiotic germ cells. Notably, HSR-9 is enriched on the chromosome pair in pachytene oogenic germ cells. HSR-9 is also present at kinetochores during both mitotic and meiotic divisions but does not appear to be essential for monitoring microtubule-kinetochore attachments or tension. Using cytological markers of different steps in recombinational repair, we found that HSR-9 influences the processing of a subset of meiotic double strand breaks into COSA-1-marked crossovers. Additionally, HSR-9 plays a role in meiotic chromosome segregation under conditions where chromosomes fail to pair, synapse, and recombine. Together, these results highlight that chromatin-associated HSR-9 has both conserved and unique functions in the regulation of meiotic chromosome behavior.
PubMed: 38659880
DOI: 10.1101/2024.04.12.589267 -
Genes To Cells : Devoted To Molecular &... Jun 2024Interhomolog recombination in meiosis is mediated by the Dmc1 recombinase. The Mei5-Sae3 complex of Saccharomyces cerevisiae promotes Dmc1 assembly and functions with...
Interhomolog recombination in meiosis is mediated by the Dmc1 recombinase. The Mei5-Sae3 complex of Saccharomyces cerevisiae promotes Dmc1 assembly and functions with Dmc1 for homology-mediated repair of meiotic DNA double-strand breaks. How Mei5-Sae3 facilitates Dmc1 assembly remains poorly understood. In this study, we created and characterized several mei5 mutants featuring the amino acid substitutions of basic residues. We found that Arg97 of Mei5, conserved in its ortholog, SFR1 (complex with SWI5), RAD51 mediator, in humans and other organisms, is critical for complex formation with Sae3 for Dmc1 assembly. Moreover, the substitution of either Arg117 or Lys133 with Ala in Mei5 resulted in the production of a C-terminal truncated Mei5 protein during yeast meiosis. Notably, the shorter Mei5-R117A protein was observed in meiotic cells but not in mitotic cells when expressed, suggesting a unique regulation of Dmc1-mediated recombination by posttranslational processing of Mei5-Sae3.
PubMed: 38924305
DOI: 10.1111/gtc.13138 -
Genetics Jun 202453BP1 plays a crucial role in regulating DNA damage repair pathway choice and checkpoint signaling in somatic cells; however, its role in meiosis has remained enigmatic....
53BP1 plays a crucial role in regulating DNA damage repair pathway choice and checkpoint signaling in somatic cells; however, its role in meiosis has remained enigmatic. In this study, we demonstrate that the Caenorhabditis elegans ortholog of 53BP1, HSR-9, associates with chromatin in both proliferating and meiotic germ cells. Notably, HSR-9 is enriched on the X chromosome pair in pachytene oogenic germ cells. HSR-9 is also present at kinetochores during both mitotic and meiotic divisions but does not appear to be essential for monitoring microtubule-kinetochore attachments or tension. Using cytological markers of different steps in recombinational repair, we found that HSR-9 influences the processing of a subset of meiotic double strand breaks into COSA-1-marked crossovers. Additionally, HSR-9 plays a role in meiotic X chromosome segregation under conditions where X chromosomes fail to pair, synapse, and recombine. Together, these results highlight that chromatin-associated HSR-9 has both conserved and unique functions in the regulation of meiotic chromosome behavior.
PubMed: 38884610
DOI: 10.1093/genetics/iyae102