Carboxyl Methylation-Demethylation of Nonhistone Chromosomal Proteins
Isaac Bekhor, Carol J. Mirell, C. C. Liew in Progress in Nonhistone Protein Research, 1985
When the nucleoplasmic fraction was incubated with AdoMet several of the proteins served as methyl acceptors (Table 1). This observation led us to propose that methylation of specific carboxyl side chains would alter the charge and allow these proteins to bind to DNA.30 The rapid reversal of this reaction via a protein methylesterase could account for the presence of methyl-acceptor proteins in the nucleoplasm in the absence of protein synthesis. The presence of PME in the nuclei could be readily demonstrated upon inhibition of the PCM with AdoHcy. The majority of the PME was bound to the chromatin, since removal of the nucleoplasmic proteins did not alter the rate of demethylation. The chromosomalbound PME yielded some 3 pmol [3H]methanol per milligram of protein per minute (Figure 4). This activity was some tenfold higher than the endogenous activity observed with either cytoplasm of nucleoplasm (data not presented).
Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
It was postulated that immediate disruption of the nucleolin ribosomal RNA G-quadruplex interaction by quarfloxin led to selective inhibition of Pol I-driven transcription. Also, the re-localization of nucleolin to the nucleoplasm was known to be a common response to cellular stress, resulting in selective apoptosis through various different pathways. Interestingly, it has been shown that nucleolin has significant selectivity for the myc G-quadruplex, where it inhibits myc transcription. In early experiments, although quarfloxin did not inhibit myc gene expression in A549 cells growing in vitro after 2 hours of exposure, in other studies the molecule was shown to inhibit myc mRNA expression by 85% in HCT-116 tumor cells isolated from mice after treatment with quarfloxin.
Role of Nonhistone Chromosomal Proteins in Selective Gene Expression
Gerald M. Kolodny in Eukaryotic Gene Regulation, 2018
A basic question to be answered is whether activation of genes is brought about by newly synthesized nonhistone chromosomal proteins or by modifications of preexisting genome-associated nonhistone chromosomal proteins. Alternatively, proteins residing in the cytoplasm or in the nucleoplasm may be modified in such a manner that they become associated with the genome and thereby render genes transcribable. Johnson and co-workers have observed that activation of lymphocytes by mitogenic agents results in accumulation of preexisting cytoplasmic proteins in the nucleus.365 A nucleo-plasmic pool of nonhistone chromosomal proteins has also been reported.147 These latter two observations are consistent with the possibility that alterations in gene readout involve recruitment of proteins from the cytoplasm or nucleoplasm and their subsequent association with the genome. However, other studies suggest that protein synthesis is required for activation of transcription in human diploid fibroblasts following stimulation to proliferate.555 In addition to numerous correlations between posttranslational modifications of nonhistone chromosomal proteins and changes in gene readout, recent studies suggest that the phosphate groups on nonhistone chromosomal proteins are important in rendering histone genes transcribable.140,545
Mechanism of Elian granules in the treatment of precancerous lesions of gastric cancer in rats through the MAPK signalling pathway based on network pharmacology
Published in Pharmaceutical Biology, 2022
Zhirong Yi, Qingling Jia, Yili Lin, Yujiao Wang, Jun Cong, Zhijian Gu, Jianghong Ling, Gan Cai
To further understand the pharmacological mechanism of Elian granules on PLGC, GO function, and KEGG pathway enrichment analyses of the 190 common targets were carried out using the DAVID database. The threshold was set at P < 0.05. We found the biological process function was mainly related to positive regulation of transcription DNA-templated, and drug response. The cellular component was primarily associated with the cytosol, extracellular space, and nucleoplasm. The molecular function was found mainly related to enzyme binding, identical protein binding, and transcription factor binding (Figure 5). KEGG analysis results showed that the treatment of PLGC with Elian granules was mainly related to autophagy and inflammation. The top 10 pathways were the PI3K-Akt, MAPK, FoxO, Ras, TNF, HIF-1, T cell receptor, Toll-like receptor, p53, and prolactin signalling pathways (Figure 6).
Polystyrene nanoparticles: the mechanism of their genotoxicity in human peripheral blood mononuclear cells
Published in Nanotoxicology, 2022
Kinga Malinowska, Bożena Bukowska, Ireneusz Piwoński, Marek Foksiński, Aneta Kisielewska, Ewelina Zarakowska, Daniel Gackowski, Paulina Sicińska
Similarly, the analysis by Zheng, Yuan, and Chunguang (2019) showed DNA damage in rat liver cells (C57BL6-J) exposed to PS-NPs at 5 and 10 µM. Other researchers detected DNA damage in the Hs27 (human fibroblasts) cell line exposed to PS-NPs at 75 µg/mL using the cytokine block micronucleus (CBMN) assay (Poma et al. 2019). In turn, Vecchiotti et al. (2021) showed the formation of micronuclei in colorectal adenocarcinoma cells (HCT116) exposed to high concentrations (800 and 1200 µg/mL) of PS-NPs (100 nm), which indicated their low genotoxic potential. In addition, they observed formation of nuclear buds and protrusions of nucleoplasm. Other studies used white carp (Ctenopharyngodon idella), which was exposed to PS-NPs at 0.04, 34, and 34 µg/L for 20 days. The results showed DNA damage in red blood cells of studied fish (Guimarães et al. 2021). Subsequent studies conducted by Alaraby et al. (2022) revealed a significant increase in the level of DNA damage in Drosophila larvae exposed to PS particles at doses of 0.4 and 2 mg/g of food. They also showed that the exposure to NPs with a diameter of 50 nm induced a higher level of DNA damage than in the case of particles with a diameter of 200 and 500 nm. The above mentioned results are consistent with other studies by Gopinath et al. (2019), Shah et al. (2020), and Brandts et al. (2018) who showed that damage to the genetic material increased along with increasing doses of PS-NPs given to Allium cepa, Ctenopharyngodon Idella, and Mytilus galloprovincialis.
Developments in pharmacotherapeutic agents for hepatitis B – how close are we to a functional cure?
Published in Expert Opinion on Pharmacotherapy, 2023
Naoshin Khan, Mohamed Ramzi Almajed, Mary Grace Fitzmaurice, Syed-Mohammed Jafri
Understanding the HBV replication cycle allows the development of agents to target various key steps to prevent and mitigate the infection [Figure 1]. HBV attaches to surface cell-associated heparan sulfate proteoglycans and binds to hepatocyte surface receptors. Endocytosis and fusion of the viral envelope occurs at the cellular surface, releasing the viral nucleocapsid into the cytoplasm; entry inhibitors target this step. The nucleocapsid is transported along cellular microtubules to the nucleus where viral DNA is released into the nucleoplasm. Viral DNA undergoes repair by viral polymerases and cellular enzymes to create covalently closed circular DNA (cccDNA) which acts as a template for transcription within the cell. cccDNA utilizes the host cell’s transcription processes to create the viral RNA needed for viral protein production and replication. Viral RNA is then transported to the cytoplasm where it undergoes translation to produce viral proteins; small interfering RNAs target this step. Viral proteins and nuclear material then forms new HBV RNA-containing nucleocapsids; capsid inhibitors and capsid assembly modulators target this step. Polymerases convert these into DNA-containing nucleocapsids; polymerase inhibitors such as nucleos(t)ide analogs and non-nucleos(t)ide analogs target this step. Novel nucleocapsids are thereafter either imported back into the nucleolus where they replicate further or enveloped and secreted out of the cell; HbsAg inhibitors target this step [9,10].
Related Knowledge Centers
- Cytoplasm
- Eukaryote
- Nuclear Envelope
- Protein
- Protoplasm
- Cell Nucleus
- Organelle
- Nucleolus
- Chromosome
- Nuclear Bodies