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8. Structural basis for substrate selection by the SARS-CoV-2 replicase

Author

Malone, Brandon F., Perry, Jason K., Olinares, Paul Dominic B., Lee, Hery W., Chen, James, Appleby, Todd C., Feng, Joy Y., Bilello, John P., Ng, Honkit, Sotiris, Johanna, Ebrahim, Mark, Chua, Eugene Y. D., Mendez, Joshua H., Eng, Ed T., Landick, Robert, Götte, Matthias, Chait, Brian T., Campbell, Elizabeth A., and Darst, Seth A.

Published
2023
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11. Mechanisms of Transcriptional Pausing in Bacteria

Author

Kang, Jin Young, Mishanina, Tatiana V, Landick, Robert, and Darst, Seth A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Bacteria, DNA, Bacterial, DNA-Directed RNA Polymerases, Gene Expression Regulation, Bacterial, Nucleic Acid Conformation, Protein Conformation, Transcription Factors, Transcription, Genetic, Backtrack pause, Elemental pause, NusA, NusG, RNA hairpin pause, Medicinal and Biomolecular Chemistry, Microbiology, Biochemistry & Molecular Biology, Biochemistry and cell biology
Abstract

Pausing by RNA polymerase (RNAP) during transcription regulates gene expression in all domains of life. In this review, we recap the history of transcriptional pausing discovery, summarize advances in our understanding of the underlying causes of pausing since then, and describe new insights into the pausing mechanisms and pause modulation by transcription factors gained from structural and biochemical experiments. The accumulated evidence to date suggests that upon encountering a pause signal in the nucleic-acid sequence being transcribed, RNAP rearranges into an elemental, catalytically inactive conformer unable to load NTP substrate. The conformation, and as a consequence lifetime, of an elemental paused RNAP is modulated by backtracking, nascent RNA structure, binding of transcription regulators, or a combination of these mechanisms. We conclude the review by outlining open questions and directions for future research in the field of transcriptional pausing.

Published
2019

15. The elemental mechanism of transcriptional pausing.

Author

Saba, Jason, Chua, Xien Yu, Mishanina, Tatiana V, Nayak, Dhananjaya, Windgassen, Tricia A, Mooney, Rachel Anne, and Landick, Robert

Subjects
Nucleotides, DNA, RNA, Transcription, Genetic, Base Sequence, Consensus Sequence, Base Pairing, Kinetics, Mutation, Templates, Genetic, Transcription Elongation, Genetic, E. coli, RNA polymerase, biochemistry, chemical biology, chromosomes, gene expression, gene regulation, transcription, Transcription, Genetic, Templates, Transcription Elongation, Biochemistry and Cell Biology
Abstract

Transcriptional pausing underlies regulation of cellular RNA biogenesis. A consensus pause sequence that acts on RNA polymerases (RNAPs) from bacteria to mammals halts RNAP in an elemental paused state from which longer-lived pauses can arise. Although the structural foundations of pauses prolonged by backtracking or nascent RNA hairpins are recognized, the fundamental mechanism of the elemental pause is less well-defined. Here we report a mechanistic dissection that establishes the elemental pause signal (i) is multipartite; (ii) causes a modest conformational shift that puts γ-proteobacterial RNAP in an off-pathway state in which template base loading but not RNA translocation is inhibited; and (iii) allows RNAP to enter pretranslocated and one-base-pair backtracked states easily even though the half-translocated state observed in paused cryo-EM structures rate-limits pause escape. Our findings provide a mechanistic basis for the elemental pause and a framework to understand how pausing is modulated by sequence, cellular conditions, and regulators.

Published
2019

16. Natural Variation in the Multidrug Efflux Pump SGE1 Underlies Ionic Liquid Tolerance in Yeast

Author

Higgins, Douglas A, Young, Megan KM, Tremaine, Mary, Sardi, Maria, Fletcher, Jenna M, Agnew, Margaret, Liu, Lisa, Dickinson, Quinn, Peris, David, Wrobel, Russell L, Hittinger, Chris Todd, Gasch, Audrey P, Singer, Steven W, Simmons, Blake A, Landick, Robert, Thelen, Michael P, and Sato, Trey K

Subjects
Microbiology, Biological Sciences, Genetics, Industrial Biotechnology, Human Genome, Biotechnology, Drug Tolerance, Genetic Variation, Imidazoles, Ionic Liquids, Membrane Proteins, Membrane Transport Proteins, Phenotype, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, yeast, ionic liquid, natural variation, major facilitator superfamily, biofuels, toxin tolerance, Developmental Biology, Biochemistry and cell biology
Abstract

Imidazolium ionic liquids (IILs) have a range of biotechnological applications, including as pretreatment solvents that extract cellulose from plant biomass for microbial fermentation into sustainable bioenergy. However, residual levels of IILs, such as 1-ethyl-3-methylimidazolium chloride ([C2C1im]Cl), are toxic to biofuel-producing microbes, including the yeast Saccharomyces cerevisiae. S. cerevisiae strains isolated from diverse ecological niches differ in genomic sequence and in phenotypes potentially beneficial for industrial applications, including tolerance to inhibitory compounds present in hydrolyzed plant feedstocks. We evaluated >100 genome-sequenced S. cerevisiae strains for tolerance to [C2C1im]Cl and identified one strain with exceptional tolerance. By screening a library of genomic DNA fragments from the [C2C1im]Cl-tolerant strain for improved IIL tolerance, we identified SGE1, which encodes a plasma membrane multidrug efflux pump, and a previously uncharacterized gene that we named ionic liquid tolerance 1 (ILT1), which encodes a predicted membrane protein. Analyses of SGE1 sequences from our panel of S. cerevisiae strains together with growth phenotypes implicated two single nucleotide polymorphisms (SNPs) that associated with IIL tolerance and sensitivity. We confirmed these phenotypic effects by transferring the SGE1 SNPs into a [C2C1im]Cl-sensitive yeast strain using CRISPR/Cas9 genome editing. Further studies indicated that these SNPs affect Sge1 protein stability and cell surface localization, influencing the amount of toxic IILs that cells can pump out of the cytoplasm. Our results highlight the general potential for discovering useful biotechnological functions from untapped natural sequence variation and provide functional insight into emergent SGE1 alleles with reduced capacities to protect against IIL toxicity.

Published
2018

28. A pause sequence enriched at translation start sites drives transcription dynamics in vivo

Author

Larson, Matthew H, Mooney, Rachel A, Peters, Jason M, Windgassen, Tricia, Nayak, Dhananjaya, Gross, Carol A, Block, Steven M, Greenleaf, William J, Landick, Robert, and Weissman, Jonathan S

Subjects
Genetics, Human Genome, Emerging Infectious Diseases, Base Sequence, Codon, Initiator, Consensus Sequence, DNA-Directed RNA Polymerases, Escherichia coli, Gene Expression Regulation, Bacterial, Peptide Chain Initiation, Translational, Regulatory Elements, Transcriptional, Transcription, Genetic, General Science & Technology
Abstract

Transcription by RNA polymerase (RNAP) is interrupted by pauses that play diverse regulatory roles. Although individual pauses have been studied in vitro, the determinants of pauses in vivo and their distribution throughout the bacterial genome remain unknown. Using nascent transcript sequencing, we identified a 16-nucleotide consensus pause sequence in Escherichia coli that accounts for known regulatory pause sites as well as ~20,000 new in vivo pause sites. In vitro single-molecule and ensemble analyses demonstrate that these pauses result from RNAP-nucleic acid interactions that inhibit next-nucleotide addition. The consensus sequence also leads to pausing by RNAPs from diverse lineages and is enriched at translation start sites in both E. coli and Bacillus subtilis. Our results thus reveal a conserved mechanism unifying known and newly identified pause events.

Published
2014

37. RNA polymerase motions during promoter melting

Author

Feklistov, Andrey, Bae, Brian, Hauver, Jesse, Lass-Napiorkowska, Agnieszka, Kalesse, Markus, Glaus, Florian, Altmann, Karl-Heinz, Heyduk, Tomasz, Landick, Robert, and Darst, Seth A.

Published
2017

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