A Feedback Regulatory Loop Containing McdR and WhiB2 Controls Cell Division and DNA Repair in Mycobacteria

Zhou, Wei; Huang, Shuo; Cumming, Bridgette M.; Zhang, Yong; Tang, Wei; Steyn, Adrie J. C.; Chen, Shiyun; Hu, Yangbo

doi:10.1128/mbio.03343-21

Cited by 6 publications

(9 citation statements)

References 69 publications

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“…S1 panels 2 nd day, 4 th day and 8 th day). Furthermore, the expression of the cell division checkpoint regulator of mycobacteria ( MSMEG_3644 ) that functions as a transcriptional activator of dnaE2 was also induced by ∼5 folds during biofilm formation (Table-2) 37 .…”

Section: Resultsmentioning

confidence: 99%

“…To understand the rationale behind this inconsistency we looked for potential regulators that could induce dnaE2 . A recent study has shown that over-expression of a MerR family transcription regulator Rv1830 (MSMEG_3644) acts as a mycobacterial cell cycle checkpoint by preventing mycobacterial cell division and simultaneously induces expression of dnaE2 and imuB 37 . Our RNA-Seq data revealed that the expression of MSMEG_3644 was induced by ∼5 folds in the biofilm stage but was repressed during the recovery stage (Table-2).…”

Section: Discussionmentioning

confidence: 99%

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dnaE2expression promotes genetic diversity and bacterial persistence in mycobacterial biofilms

Kurthkoti

Salini

Bhat

et al. 2022

Preprint

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The complex cellular architecture and the microenvironments within the biofilm give rise to a population that is both physiologically and genetically heterogenous. Transcriptome analysis of Mycobacterium smegmatis in biofilm culture and its transition phase into planktonic growth was performed to identify the genetic basis of heterogeneity in the biofilm. While there was an increase in the expression of mycobacterial mutasome consisting of dnaE2, imuA and imuB in the biofilm, the mutation burden was less compared to planktonic culture. Deletion of dnaE2 displays lower mutation frequency and bacterial fitness in comparison to the parental strain in biofilm culture. The expression of dnaE2 contributes to slower bacterial growth rate, potentially promoting persister formation. Our study uncovers the multiple benefits of dnaE2 expression in biofilm such as increasing genetic diversity and reducing growth rate; both of which are necessary for mycobacterial survival and adaptation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

dnaE2expression promotes genetic diversity and bacterial persistence in mycobacterial biofilms

Kurthkoti

Salini

Bhat

et al. 2022

Preprint

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“…As we demonstrated that CvkR binding in P tnsB overlaps the TSS of P tnsB , and partially the -10 element, CvkR should regulate the expression of tnsB in a different way from cas12k . Actually, a few MerR-type regulators indeed have been reported to function as transcription repressors and regulate gene expression in significantly different ways, such as BldC 61 , HnoC 62 , and McdR 63 . BldC binds DNA direct repeats as cooperative multimers to regulate gene expression, while both HnoC and McdR are instances of regulators recognizing palindromic motifs overlapping TSS and -10 elements.…”

Section: Discussionmentioning

confidence: 99%

“…We even noticed a 20-nt long −10/−35 spacer in the promoter of one of the HnoC targets, hnoD , suggesting a possible similar regulatory mechanism of interfering with association of the RNAP holoenzyme and transcription initiation rather than reshaping of promoter DNA 62 . McdR, another MerR type repressor involved in controlling cell division, DNA repair, drug resistance and other stress responses in Mycobacteria, could also repress target promoters in this manner 63 . Moreover, the here investigated cyanobacterial CvkR shows 33% sequence identity with mycobacterial McdR (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

CvkR is a MerR-type transcriptional repressor of class 2 type V-K CRISPR-associated transposase systems

et al. 2023

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Certain CRISPR-Cas elements integrate into Tn7-like transposons, forming CRISPR-associated transposon (CAST) systems. How the activity of these systems is controlled in situ has remained largely unknown. Here we characterize the MerR-type transcriptional regulator Alr3614 that is encoded by one of the CAST (AnCAST) system genes in the genome of cyanobacterium Anabaena sp. PCC 7120. We identify a number of Alr3614 homologs across cyanobacteria and suggest naming these regulators CvkR for Cas V-K repressors. Alr3614/CvkR is translated from leaderless mRNA and represses the AnCAST core modules cas12k and tnsB directly, and indirectly the abundance of the tracr-CRISPR RNA. We identify a widely conserved CvkR binding motif 5’-AnnACATnATGTnnT-3’. Crystal structure of CvkR at 1.6 Å resolution reveals that it comprises distinct dimerization and potential effector-binding domains and that it assembles into a homodimer, representing a discrete structural subfamily of MerR regulators. CvkR repressors are at the core of a widely conserved regulatory mechanism that controls type V-K CAST systems.

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“…WhiB4 regulates b-lactamase expression, thus inducing antibiotic tolerance in M. tuberculosis (Mishra et al, 2017). WhiB2 is part of a regulatory loop involving rv1830 (mcdR) ultimately fine-tuning mycobacterial cell division and adaptation to stress response, including increased mutation rates during antibiotic challenge (Zhou et al, 2022). Recent genome-wide association analysis (GWAS) approaches have also identified novel associations between mutations in the whiB6 region and aminoglycosides resistance (Farhat et al, 2019).…”

Section: Whib Family (Whib1-7)mentioning

confidence: 99%

Transcriptional regulation and drug resistance in Mycobacterium tuberculosis

Miotto

Sorrentino

Giorgi

et al. 2022

Front. Cell. Infect. Microbiol.

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Bacterial drug resistance is one of the major challenges to present and future human health, as the continuous selection of multidrug resistant bacteria poses at serious risk the possibility to treat infectious diseases in the near future. One of the infection at higher risk to become incurable is tuberculosis, due to the few drugs available in the market against Mycobacterium tuberculosis. Drug resistance in this species is usually due to point mutations in the drug target or in proteins required to activate prodrugs. However, another interesting and underexplored aspect of bacterial physiology with important impact on drug susceptibility is represented by the changes in transcriptional regulation following drug exposure. The main regulators involved in this phenomenon in M. tuberculosis are the sigma factors, and regulators belonging to the WhiB, GntR, XRE, Mar and TetR families. Better understanding the impact of these regulators in survival to drug treatment might contribute to identify new drug targets and/or to design new strategies of intervention.

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A Feedback Regulatory Loop Containing McdR and WhiB2 Controls Cell Division and DNA Repair in Mycobacteria

Abstract: Drug-resistant M. tuberculosis poses a threat to the control and prevention of tuberculosis (TB) worldwide. Thus, there is a need to identify the mechanisms enabling M. tuberculosis to adapt and grow under drug-induced stress.

Cited by 6 publications

References 69 publications

dnaE2expression promotes genetic diversity and bacterial persistence in mycobacterial biofilms

dnaE2expression promotes genetic diversity and bacterial persistence in mycobacterial biofilms

CvkR is a MerR-type transcriptional repressor of class 2 type V-K CRISPR-associated transposase systems

Transcriptional regulation and drug resistance in Mycobacterium tuberculosis

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