scholarly journals Intrusion of a DNA Repair Protein in the RNome World: Is This the Beginning of a New Era?

2009 ◽  
Vol 30 (2) ◽  
pp. 366-371 ◽  
Author(s):  
Gianluca Tell ◽  
David M. Wilson ◽  
Chow H. Lee
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Mrna Level ◽  
Rna Metabolism ◽  
Coding Region ◽  
Control Of Gene Expression ◽  
Dna And Rna ◽  
New Findings

ABSTRACT Apurinic/apyrimidinic endonuclease 1 (APE1), an essential protein in mammals, is known to be involved in base excision DNA repair, acting as the major abasic endonuclease; the protein also functions as a redox coactivator of several transcription factors that regulate gene expression. Recent findings highlight a novel role for APE1 in RNA metabolism. The new findings are as follows: (i) APE1 interacts with rRNA and ribosome processing protein NPM1 within the nucleolus; (ii) APE1 interacts with proteins involved in ribosome assembly (i.e., RLA0, RSSA) and RNA maturation (i.e., PRP19, MEP50) within the cytoplasm; (iii) APE1 cleaves abasic RNA; and (iv) APE1 cleaves a specific coding region of c-myc mRNA in vitro and influences c-myc mRNA level and half-life in cells. Such findings on the role of APE1 in the posttranscriptional control of gene expression could explain its ability to influence diverse biological processes and its relocalization to cytoplasmic compartments in some tissues and tumors. In addition, we propose that APE1 serves as a “cleansing” factor for oxidatively damaged abasic RNA, establishing a novel connection between DNA and RNA surveillance mechanisms. In this review, we introduce questions and speculations concerning the role of APE1 in RNA metabolism and discuss the implications of these findings in a broader evolutionary context.

scholarly journals The Mycobacterium tuberculosis sRNA F6 regulates expression of groEL/S

2020 ◽  
Author(s):  
Joanna Houghton ◽  
Angela Rodgers ◽  
Graham Rose ◽  
Kristine B. Arnvig
Keyword(s):  
Gene Expression ◽  
Mycobacterium Tuberculosis ◽  
Small Rnas ◽  
Transcriptional Control ◽  
Cold Shock ◽  
Control Of Gene Expression ◽  
Rna Biology ◽  
Mouse Model Of Infection

ABSTRACTAlmost 140 years after the identification of Mycobacterium tuberculosis as the etiological agent of tuberculosis, important aspects of its biology remain poorly described. Little is known about the role of post-transcriptional control of gene expression and RNA biology, including the role of most of the small RNAs (sRNAs) identified to date. We have carried out a detailed investigation of the M. tuberculosis sRNA, F6, and show it to be dependent on SigF for expression and significantly induced during in vitro starvation and in a mouse model of infection. However, we found no evidence of attenuation of a ΔF6 strain within the first 20 weeks of infection. A further exploration of F6 using in vitro models of infection suggests a role for F6 as a highly specific regulator of the heat shock repressor, HrcA. Our results point towards a role for F6 during periods of low metabolic activity similar to cold shock and associated with nutrient starvation such as that found in human granulomas in later stages of infection.

scholarly journals Role of RelA of Streptococcus mutans in Global Control of Gene Expression

2007 ◽  
Vol 190 (1) ◽  
pp. 28-36 ◽  
Author(s):  
Marcelle M. Nascimento ◽  
José A. Lemos ◽  
Jacqueline Abranches ◽  
Vanessa K. Lin ◽  
Robert A. Burne
Keyword(s):  
Gene Expression ◽  
Streptococcus Mutans ◽  
Stringent Response ◽  
Phenotypic Traits ◽  
Dependent Manner ◽  
Pathogenic Potential ◽  
Control Of Gene Expression ◽  
Global Control

ABSTRACT The production of (p)ppGpp by Streptococcus mutans UA159 is catalyzed by three gene products: RelA, RelP, and RelQ. Here, we investigate the role of the RelA (Rel) homologue of S. mutans in the stringent response and in the global control of gene expression. RelA of S. mutans was shown to synthesize pppGpp in vitro from GTP and ATP in the absence of added ribosomes, as well as in vivo in an Escherichia coli relA-spoT mutant. Mupirocin (MUP) was shown to induce high levels of (p)ppGpp production in S. mutans in a relA-dependent manner, with a concomitant reduction in GTP pools. Transcription profiling after MUP treatment of S. mutans revealed that 104 genes were upregulated and 130 were downregulated (P ≤ 0.001); mainly, genes for macromolecular biosynthesis, translation, and energy metabolism were downregulated. When a derivative of UA159 carrying a complete deletion of the relA gene was treated with MUP, 72 genes were upregulated and 52 were downregulated (P ≤ 0.001). The expression of 50 genes (P ≤ 0.001) was commonly affected by MUP treatment in the two strains, suggesting that S. mutans can mount a relA-independent response to MUP. Consistent with the gene expression profiling, RelA was shown to play major roles in the regulation of phenotypic traits that are required for establishment, persistence, and virulence expression by this oral pathogen. Thus, RelA is the major (p)ppGpp synthase controlling the stringent response in S. mutans, and it coordinates the expression of genes and phenotypes that contribute to the pathogenic potential of the organism.

scholarly journals DNA Methylation and Chromatin: Role(s) of Methyl-CpG-Binding Protein ZBTB38

2018 ◽  
Vol 11 ◽  
pp. 251686571881111 ◽  
Author(s):  
Maud de Dieuleveult ◽  
Benoit Miotto
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factors ◽  
Dna Sequences ◽  
Mammalian Cells ◽  
Expression Patterns ◽  
Control Of Gene Expression ◽  
Methylated Dna

DNA methylation plays an essential role in the control of gene expression during early stages of development as well as in disease. Although many transcription factors are sensitive to this modification of the DNA, we still do not clearly understand how it contributes to the establishment of proper gene expression patterns. We discuss here the recent findings regarding the biological and molecular function(s) of the transcription factor ZBTB38 that binds methylated DNA sequences in vitro and in cells. We speculate how these findings may help understand the role of DNA methylation and DNA methylation–sensitive transcription factors in mammalian cells.

scholarly journals NusG controls transcription pausing and RNA polymerase translocation throughout theBacillus subtilisgenome

2020 ◽  
Vol 117 (35) ◽  
pp. 21628-21636 ◽  
Author(s):  
Alexander V. Yakhnin ◽  
Peter C. FitzGerald ◽  
Carl McIntosh ◽  
Helen Yakhnin ◽  
Maria Kireeva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase ◽  
Transcription Elongation ◽  
Elongation Factor ◽  
Flavin Mononucleotide ◽  
Protein Coding ◽  
Control Of Gene Expression ◽  
Genome Wide

Transcription is punctuated by RNA polymerase (RNAP) pausing. These pauses provide time for diverse regulatory events that can modulate gene expression. Transcription elongation factors dramatically affect RNAP pausing in vitro, but the genome-wide role of such factors on pausing has not been examined. Using native elongating transcript sequencing followed by RNase digestion (RNET-seq), we analyzed RNAP pausing inBacillus subtilisgenome-wide and identified an extensive role of NusG in pausing. This universally conserved transcription elongation factor is known as Spt5 in archaeal and eukaryotic organisms.B. subtilisNusG shifts RNAP to the posttranslocation register and induces pausing at 1,600 sites containing a consensus TTNTTT motif in the nontemplate DNA strand within the paused transcription bubble. The TTNTTT motif is necessary but not sufficient for NusG-dependent pausing. Approximately one-fourth of these pause sites were localized to untranslated regions and could participate in posttranscription initiation control of gene expression as was previously shown fortlrBand thetrpEDCFBAoperon. Most of the remaining pause sites were identified in protein-coding sequences. NusG-dependent pausing was confirmed for all 10 pause sites that we tested in vitro. Putative pause hairpins were identified for 225 of the 342 strongest NusG-dependent pause sites, and some of these hairpins were shown to function in vitro. NusG-dependent pausing in theribDriboswitch provides time for cotranscriptional binding of flavin mononucleotide, which decreases the concentration required for termination upstream of theribDcoding sequence. Our phylogenetic analysis implicates NusG-dependent pausing as a widespread mechanism in bacteria.

The Role of DNA Repair Complex DNA-PK in HIV-1 Transcription

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 133
Author(s):  
Olga Shadrina ◽  
Andrey Anisenko ◽  
Marina Gottikh
Keyword(s):  
Dna Repair ◽  
Transcription Factors ◽  
Firefly Luciferase ◽  
Coding Region ◽  
Dna Breaks ◽  
Rnp Complex ◽  
The Impact ◽  
Hiv 1

The human DNA-dependent protein kinase (DNA-PK), composed of the heterodimeric protein Ku and catalytic subunit DNA-PKcs, is a sensor of double-strand DNA breaks in the non-homologous end-joining DNA repair pathway. The key role of DNA-PK in the post-integrational repair of HIV-1 has been shown. It has also been suggested that DNA-PK can participate in the regulation of HIV transcription, although the mechanism is unclear. To clarify the impact of each DNA-PK subunit on the transcription of HIV-1, HEK 293T cells, in which each of the DNA-PK components was depleted, were transfected with reporter vectors containing firefly luciferase under the control of HIV LTR promoter. We detected a positive influence of both Ku subunits, but not of DNA-PKcs, on the transcription from the HIV promoter. Ku is known to interact with HIV-1 TAR RNA, playing an essential role in viral transcription; nonetheless, the deletion of the TAR-coding region from LTR did not alter the Ku effect. Human small noncoding 7SK RNA participates in HIV-1 transcription. The direct binding of recombinant Ku and in vitro transcribed 7SK RNA was demonstrated using EMSA. In addition, we identified the interactions of endogenous Ku with proteins HEXIM1 and Cdk9 from the 7SK RNP complex. These results suggest that Ku exerts its effects on HIV-1 transcription via interaction with the 7SK RNP complex. However, we cannot rule out an indirect effect of Ku on transcription via the regulation of the levels of some transcription factors participating in HIV-1 transcription. We performed a transcriptome analysis of wild type HEK 293T cells and those with depleted DNA-PK subunits. The genes regulated by each subunit were defined and the genes that were mainly dependent on Ku subunits were selected. Among them, we identified transcription factors enhancing HIV-1 transcription, whose levels were downregulated in Ku-depleted cells. The study was supported by RFBR grant №18-04-00542 and RSF grant №17-14-01107.

Activation of bovine oocytes by protein synthesis inhibitors: new findings on the role of MPF/MAPKs†

2021 ◽  
Author(s):  
Cecilia Valencia ◽  
Felipe Alonso Pérez ◽  
Carola Matus ◽  
Ricardo Felmer ◽  
María Elena Arias
Keyword(s):  
Protein Synthesis ◽  
Kinase Activity ◽  
Cyclin B1 ◽  
Protein Synthesis Inhibitors ◽  
Vitro Fertilization ◽  
New Findings ◽  
Bovine Oocytes ◽  
Dependent Pathway

Abstract The present study evaluated the mechanism by which protein synthesis inhibitors activate bovine oocytes. The aim was to analyze the dynamics of MPF and MAPKs. MII oocytes were activated with ionomycin (Io), ionomycin+anisomycin (ANY) and ionomycin+cycloheximide (CHX) and by in vitro fertilization (IVF). The expression of cyclin B1, p-CDK1, p-ERK1/2, p-JNK, and p-P38 were evaluated by immunodetection and the kinase activity of ERK1/2 was measured by enzyme assay. Evaluations at 1, 4, and 15 hours postactivation (hpa) showed that the expression of cyclin B1 was not modified by the treatments. ANY inactivated MPF by p-CDK1Thr14-Tyr15 at 4 hpa (P < 0.05), CHX increased pre-MPF (p-CDK1Thr161 and p-CDK1Thr14-Tyr15) at 1 hpa and IVF increased p-CDK1Thr14-Tyr15 at 17 hours postfertilization (hpf) (P < 0.05). ANY and CHX reduced the levels of p-ERK1/2 at 4 hpa (P < 0.05) and its activity at 4 and 1 hpa, respectively (P < 0.05). Meanwhile, IVF increased p-ERK1/2 at 6 hpf (P < 0.05); however, its kinase activity decreased at 6 hpf (P < 0.05). p-JNK in ANY, CHX, and IVF oocytes decreased at 4 hpa (P < 0.05). p-P38 was only observed at 1 hpa, with no differences between treatments. In conclusion, activation of bovine oocytes by ANY, CHX, and IVF inactivates MPF by CDK1-dependent specific phosphorylation without cyclin B1 degradation. ANY or CHX promoted this inactivation, which seemed to be more delayed in the physiological activation (IVF). Both inhibitors modulated MPF activity via an ERK1/2-independent pathway, whereas IVF activated the bovine oocytes via an ERK1/2-dependent pathway. Finally, ANY does not activate the JNK and P38 kinase pathways.

scholarly journals The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma

2021 ◽  
Vol 20 ◽  
pp. 153303382199528
Author(s):  
Qing Lv ◽  
Qinghua Xia ◽  
Anshu Li ◽  
Zhiyong Wang
Keyword(s):  
Tumor Microenvironment ◽  
Interleukin 1 ◽  
Mrna Level ◽  
Inflammatory Factors ◽  
Stomach Carcinoma ◽  
Downstream Target ◽  
Volume Weight

This study was performed to investigate the role of interleukin-1 receptor accessory protein (IL1RAP) in stomach carcinoma in vitro and in vivo, determine whether IL1RAP knockdown could regulate the development of stomach carcinoma, and elucidate the relationship between IL1RAP knockdown and inflammation by tumor microenvironment-related inflammatory factors in stomach carcinoma. We first used TCGA and GEPIA systems to predict the potential function of IL1RAP. Second, western blot and RT-PCR were used to analyze the expression, or mRNA level, of IL1RAP at different tissue or cell lines. Third, the occurrence and development of stomach carcinoma in vitro and in vivo were observed by using IL1RAP knockdown lentivirus. Finally, the inflammation of stomach carcinoma in vitro and in vivo was observed. Results show that in GEPIA and TCGA systems, IL1RAP expression in STAD tumor tissue was higher than normal, and high expression of IL1RAP in STAD patients had a worse prognostic outcome. Besides, GSEA shown IL1RAP was negative correlation of apopopsis, TLR4 and NF-κB signaling pathway. We also predicted that IL1RAP may related to IL-1 s, IL-33, and IL-36 s in STAD. The IL1RAP expression and mRNA level in tumor, or MGC803, cells were increased. Furthermore, IL1RAP knockdown by lentivirus could inhibit stomach carcinoma development in vitro and in vivo through weakening tumor cell proliferation, migration, invasion, therefore reducing tumor volume, weight, and biomarker levels, and increasing apoptotic level. Finally, we found IL1RAP knockdown could increase inflammation of tumor microenvironment-related inflammatory factors of stomach carcinoma, in vitro and in vivo. Our study demonstrates that IL1RAP is possibly able to regulate inflammation and apoptosis in stomach carcinoma. Furthermore, TLR4, NF-κB, IL-1 s, IL-33, and IL-36 s maybe the downstream target factor of IL1RAP in inflammation. These results may provide a new strategy for stomach carcinoma development by regulating inflammation.

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