Archaea: A Gold Mine for Topoisomerase Diversity

Garnier, Florence; Couturier, Mohea; Débat, Hélène; Nadal, Marc

doi:10.3389/fmicb.2021.661411

Cited by 12 publications

(15 citation statements)

References 113 publications

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“…We demonstrate that Ccr-2 contains a ribbon-helix-helix DNA-binding structural motif that regulates the transcription of genes involved in diverse cellular processes including metabolism, DNA replication and repair and cell division (Figures 2-3). Particularly, Ccr-2 downregulates the transcription of important components of the Cdv (cell division) machinery CdvA and CdvB2, SegA, a component of the chromosome segregation system (Kalliomaa-Sanford et al, 2012) and the reverse gyrase TopR2 that regulates DNA supercoiling in crenarchaeota (Garnier et al, 2021). It additionally upregulates the transcription of the ribonucleotide reductase NrdA that converts ribonucleotides into deoxyribonucleotides, an essential step for DNA synthesis, and CoxM, a component of the CO dehydrogenase important for CO oxidation in Sulfolobus (Sokolova et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…In this work, we identify and characterize aCcr1, a conserved, essential protein in Sulfolobales that functions as a regulator of cell cycle progression. aCcr1 downregulates the transcription of important components of the Cdv (cell division) machinery CdvA and CdvB2, SegA, a component of the chromosome segregation system (Kalliomaa-Sanford et al, 2012) and the reverse gyrase TopR2 that regulates DNA supercoiling in crenarchaeota (Garnier et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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A clade of RHH proteins ubiquitous in Sulfolobales and their viruses regulates cell cycle progression

Cristina

Martínez-Álvarez

et al. 2022

Preprint

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Coupling of cell growth, genome replication and segregation and cell division is crucial for all living organisms, yet cell progression control is largely underexplored in archaea. In this work, we characterize a ribbon-helix-helix transcriptional regulator (gp21) of rudivirus SIRV2, which infects the hyperthermophilic crenarchaeon S. islandicus LAL14/1. This protein belongs to a clade of highly conserved proteins of the Sulfolobales with homologs in several families of crenarchaeal viruses. Overexpression of gp21 and other members of the clade including the host homolog SiL_0190, results in impairment of cell division, evidenced by growth retardation, cell enlargement and an increase in DNA content. Additionally, gp21 can either repress or induce the transcription of several genes involved in cell division, DNA replication and cellular metabolism. Both gp21 and its cellular homolog SiL_0190 bind to the motif AGTATTA present in the promoter of their target genes, which correspond to the regulatory motif previously identified in a subset of cyclic genes in S. acidocaldarius ccr-2 (Cell Cycle Regulon 2) box. We therefore rename this clade of proteins Ccr-2 and their binding motif as ccr-2 box. Our results suggest that Ccr-2 is a master regulator of the cell cycle that silences genes involved in cell division and drives progression to the S-phase in Sulfolobales, a function exploited by all known viruses to facilitate viral propagation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A clade of RHH proteins ubiquitous in Sulfolobales and their viruses regulates cell cycle progression

Cristina

Martínez-Álvarez

et al. 2022

Preprint

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“…Given the absence of a dedicated heatshock responsive transcription regulatory mechanism and the connection between chromatin organization and transcriptional activity in Sulfolobales (47), the observed dynamic regulation of DNA supercoiling and packaging could be hypothesized to play an important role in heat-shock responsive global regulation in Sulfolobales, at least on the transcriptional level. (43,44,46).…”

Section: Effects Of Heat Shock On Chromatin Organizationmentioning

confidence: 99%

Transcriptional and translational dynamics underlying heat shock response in the thermophilic CrenarchaeonSulfolobus acidocaldarius

Baes

Grünberger

Ruys

et al. 2022

Preprint

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High-temperature stress is critical for all organisms and induces a profound cellular response. For Crenarchaeota, little information is available on how heat shock affects cellular processes and on how this response is regulated. In this work, we set out to study heat shock response in the thermoacidophilic model crenarchaeonSulfolobus acidocaldarius, which thrives in volcanic hot springs and has an optimal growth temperature of 75°C. Pulse-labeling experiments demonstrated that a temperature shift to 86°C induces a drastic reduction of the transcriptional and translational activity, but that RNA and protein neosynthesis still occurs. By combining RNA sequencing and TMT-labeled mass spectrometry, an integrated mapping of the transcriptome and proteome was performed. This revealed that heat shock causes an immediate change in the gene expression profile, with RNA levels of half of the genes being affected, followed by the more subtle reprogramming of the protein landscape. A limited correlation was observed in differential expression on the RNA and protein level, suggesting that there is a prevalence of post-transcriptional and post-translational regulation upon heat shock. Furthermore, based on the finding that promoter regions of heat shock regulon genes lack a conserved DNA-binding motif, we propose that heat-shock responsive transcription regulation is likely not to be accomplished by a classical transcription factor. Instead, in contrast to histone-harboring Euryarchaeota that have heat-shock transcription factors, it is hypothesized that Sulfolobales and other histone-lacking thermophilic archaea employ an evolutionary ancient mechanism relying on temperature-responsive changes in DNA organization and compaction, induced by the action of nucleoid-associated proteins.

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“…Topoisomerases are enzymes present in all domains of life ( Bush et al, 2015 ; Garnier et al, 2021 ). The requirement of topoisomerases is due to its role in removing topological barriers that arise during important genomic processes, including transcription, replication, and recombination ( Vos et al, 2011 ; Pommier et al, 2016 ; Brochu et al, 2020 ; McKie et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Localization of Mycobacterium tuberculosis topoisomerase I C-terminal sequence motif required for inhibition by endogenous toxin MazF4

et al. 2022

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Only about half the multi-drug resistant tuberculosis (MDR-TB) cases are successfully cured. Thus, there is an urgent need of new TB treatment against a novel target. Mycobacterium tuberculosis (Mtb) topoisomerase I (TopA) is the only type IA topoisomerase in this organism and has been validated as an essential target for TB drug discovery. Toxin-antitoxin (TA) systems participate as gene regulators within bacteria. The TA systems contribute to the long-term dormancy of Mtb within the host-cell environment. Mtb’s toxin MazF4 (Rv1495) that is part of the MazEF4 TA system has been shown to have dual activities as endoribonuclease and topoisomerase I inhibitor. We have developed a complementary assay using an Escherichia coli strain with temperature-sensitive topA mutation to provide new insights into the MazF4 action. The assay showed that E. coli is not sensitive to the endoribonuclease activity of Mtb MazF4 but became vulnerable to MazF4 growth inhibition when recombinant Mtb TopA relaxation activity is required for growth. Results from the complementation by Mtb TopA mutants with C-terminal deletions showed that the lysine-rich C-terminal tail is required for interaction with MazF4. Site-directed mutagenesis is utilized to identify two lysine residues within a conserved motif in this C-terminal tail that are critical for MazF4 inhibition. We performed molecular dynamics simulations to predict the Mtb TopA-MazF4 complex. Our simulation results show that the complex is stabilized by hydrogen bonds and electrostatic interactions established by residues in the TopA C-terminal tail including the two conserved lysines. The mechanism of Mtb TopA inhibition by MazF4 could be useful for the discovery of novel inhibitors against a new antibacterial target in pathogenic mycobacteria for treatment of both TB and diseases caused by the non-tuberculosis mycobacteria (NTM).

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Archaea: A Gold Mine for Topoisomerase Diversity

Cited by 12 publications

References 113 publications

A clade of RHH proteins ubiquitous in Sulfolobales and their viruses regulates cell cycle progression

A clade of RHH proteins ubiquitous in Sulfolobales and their viruses regulates cell cycle progression

Transcriptional and translational dynamics underlying heat shock response in the thermophilic CrenarchaeonSulfolobus acidocaldarius

Localization of Mycobacterium tuberculosis topoisomerase I C-terminal sequence motif required for inhibition by endogenous toxin MazF4

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