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Genetics and Biosynthesis of Lipopolysaccharide O-Antigens
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Wendy J. Keenleyside, Chris Whitfield
The JUMPstart sequence is always found in the same orientation to the direction of transcription, an observation that, combined with its position upstream of transcription start sites, suggests a possible role in transcription. The ops subsequence is also found in the regulatory regions of a number of gram-negative operons involved in toxin production and conjugal transfer of DNA. Studies on the involvement of ops in expression of the E. coli hemolysin operon have provided an insight into a possible mechanism of transcriptional regulation and have implicated the product of the rfaH gene in this process. By examining transcription of promoter-distal genes and mRNA transcript lengths in various ops and rfaH mutants, two groups (162,163) reported evidence to support the idea that the E. coli RfaH protein interacts with ops to suppress transcription polarity. Bailey et al. (163) also reported a structural relationship between RfaH and the essential transcription/termination cofactor NusG. Based on their experimental data and this homology, these workers have proposed that RfaH regulates expression of the ops-containing operons by interacting with the cis-acting ops element and the RNA polymerase, suppressing polarity and enabling transcription to continue through the operon. More recently, Leeds and Welch (164) speculated that RfaH might interact with the RNA polymerase to help create a termination-resistant complex in a manner similar to λ N-mediated antitermination at the λnut site (165).
rDNA: Evolution Over a Billion Years
Published in S. K. Dutta, DNA Systematics, 2019
Transcription termination has been mapped to the Hind III site at the 3′ end of the 28S rRNA gene (pXlr14,180 pXlr108.175,182 Bakken et al.183 provided additional information on both transcription initiation and termination using a combination of electron microscopy, cloned sequences modified with respect to the initiation and termination sites, and microinjection of the cloned DNA into oocyte nuclei. For transcription termination a cluster of three Τ residues were found to be important. Two Τ residue clusters were located upstream from the transcription initiation site and a transcription termination (of transcription initiated in the spacer region) role was proposed for these sequences. The electron microscopic studies of Trendelenburg184 suggest that transcription termination is a two-step process involving both the release of the precursor rRNA transcript followed by the release of RNA polymerase I molecules. Trendelenburg184 defined the region of termination as consisting of three RNA polymerase I molecules with the first being associated with the precursor rRNA transcript.
Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
mtDNA transcription shows certain similarities to the bacterial system in that the initial transcription products are polycistronic. The main protein elements involved in this process are, besides POLRMT (encoded by POLRMT, 19p13.3), TFAM (encoded by TFAM, 10q21.1), TFBM2 (encoded by TFB2M, 1q44) and TEFM (encoded by TEFM, 17q11.2). TFAM is a transcription factor A binding the upstream transcription start and responsible for recruiting POLRMT. TFBM2 is also a transcription factor and is necessary to form a fully active transcription complex. TEFM is a mitochondrial transcription elongation factor responsible for the complex processivity. It also makes a link between transcription and replication. TEFM binding to the transcription complex promotes transcription but when it is absent, the primer for replication is produced26. The last core elements, mTERFs – mitochondrial termination factors (1–4) are responsible inter alia for transcription termination. mTERF1 terminates the short transcript containing rRNAs while the other ones are involved in termination of the other transcripts and also in mtDNA translation27.
Riboswitches as therapeutic targets: promise of a new era of antibiotics
Published in Expert Opinion on Therapeutic Targets, 2023
Emily Ellinger, Adrien Chauvier, Rosa A. Romero, Yichen Liu, Sujay Ray, Nils G. Walter
Recent studies have unveiled additional mechanisms of gene regulation that are mediated by riboswitches in response to their ligand and could be exploited for the design of more specific drugs targeting a specific bacterial phylum or species [74,75] (Figure 5). For instance, the TPP, FMN, and magnesium-sensing riboswitches have been found to trigger transcription termination in response to their respective ligands through the Rho transcription factor [76–78] (Figure 5(a)). Since this mechanism involves the sequestration or accessibility of the Rho binding site (i.e. Rho utilization site or rut sequence) as a function of riboswitch folding, it contrasts with polarity regulation in which the absence of translation of the nascent mRNA allows Rho-dependent transcription termination [30]. Bicyclomycin is a compound that specifically inhibits Rho activity [79,80], however, because of its low specificity toward a particular bacterial phylum, future avenues are needed that target Rho factor only in pathogenic bacteria and not in the commensal, beneficial species found in the human gut microbiome [81,82].
Flagellum and toxin phase variation impacts intestinal colonization and disease development in a mouse model of Clostridioides difficile infection
Published in Gut Microbes, 2022
Dominika Trzilova, Mercedes A. H. Warren, Nicole C. Gadda, Caitlin L. Williams, Rita Tamayo
We recently showed that the flagellar switch impacts gene expression in a mechanism acting after transcription initiation and occurring within the leader region of the flgB operon mRNA. While not fully elucidated, this regulation is dependent on Rho-mediated transcription termination that preferentially impacts flg OFF mRNA, a mechanism that requires Rho to interact with the mRNA either within or upstream of the flagellar switch.43 To minimize the risk of interfering with Rho-mediated regulation, we chose to mutate the RIR downstream of the flagellar switch. Because the starting orientation of an invertible element can impact the efficiency of inversion by a recombinase, both flg ON and flg OFF versions were created for each mutation. Three sites were selected for mutagenesis. First, we deleted 18 of the 21 bp of the flg RIR to create flg-ΔRIR ON and OFF mutant sequences, which we anticipated would prevent switch inversion;45 however, the larger deletion presents a greater risk of altering Rho-mediated regulation. Second, we chose three highly conserved CAA nucleotides in the flg RIR for substitution with GTT to create flg-3sub ON and OFF mutant sequences (Figure 1a). Third, we targeted the previously identified nucleotide where the DNA strand is cleaved by RecV to catalyze strand exchange (Figure 1a).24 This residue and the two adjacent nucleotides were deleted to create flg-Δ3 ON and OFF mutant sequences.
Genome-wide bioinformatics analysis of FMN, SAM-I, glmS, TPP, lysine, purine, cobalamin, and SAH riboswitches for their applications as allosteric antibacterial drug targets in human pathogenic bacteria
Published in Expert Opinion on Therapeutic Targets, 2019
Nikolet Pavlova, Robert Penchovsky
There are 36 different classes of riboswitches discovered for the time being. All riboswitches are classified according to their aptamer domains [1,10]. Each of the riboswitch classes regulates a specific metabolic pathway by sensing a different type of metabolites [11]. One riboswitch could be found in many different bacteria and could be repeated many times in one genome. Riboswitches control the biosynthesis of some vitamin precursors such as riboflavin, thiamin, and cobalamin; some essential amino acids, such as methionine and lysine; some nucleotides, including adenine and guanine; or other key metabolites such as glucosamine-6-phosphate (glmS). There are three basic cis-acting mechanisms of regulation of gene expression through riboswitches that have been studied – termination of transcription, translational prevention, and destabilization of mRNА (Figure 1) [1]. Riboswitches control gene expression mainly by transcription termination or prevention of translational initiation. These mechanisms act by the formation of alternative structures [6]. Riboswitches have the ability to distinguish between closely related analogs and recognize their cognate effectors with values for the apparent dissociation constant (Kd) ranging usually from lower picomolar to micromolar concentrations [12]. The riboswitch control by transcription termination is usually done through rho-independent terminators with one known exception of Rho-dependent termination [13–15].