Sound the (Smaller) Alarm: The Triphosphate Magic Spot Nucleotide pGpp

Malik, Areej; Hept, Megan A; Purcell, Erin B.

doi:10.1128/iai.00432-22

Cited by 5 publications

(9 citation statements)

References 93 publications

(222 reference statements)

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“…A previous study has shown that NCBP2 can mediate gene interactions to modify neurodevelopmental defects of the 3q29 deletion ( 52 ). Additionally, nudix hydroxylases (NUDTs) belong to the versatile, widely distributed, housecleaning enzyme family to catalyze the hydrolysis of a wide range of nucleoside pyrophosphates linked to amino acids ( 53 , 54 ). Furthermore, previous researches have reported that NUDT10 expression is associated with malignant behaviors of gastric cancer by promoting tumor cell invasion and a poor prognosis ( 55 , 56 ), whereas NUDT11 has been shown to be associated with longer survival period in liver cancer ( 57 ) and bladder cancer ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

A signature of five 7-methylguanosine-related genes is a prognostic marker for lung squamous cell carcinoma

Liu,

Wang,

Ulivi

et al. 2023

J Thorac Dis

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Background N 7 -methylguanosine (m7G) is an important posttranscriptional modification affecting mRNA and tRNA functions and stability. The genes regulating the m7G process have been previously found involved in the carcinogenesis process. We aimed to analyze the role of m7G-related genes as potential prognostic markers for lung squamous cell carcinoma (LSCC). Methods Twenty-nine m7G-related genes were selected for the analysis in the LSCC cohort of the Cancer Genome Atlas (TCGA). Univariate, multivariate, and Kaplan-Meier analyses were used to evaluate the predictive value of risk model developed with m7G signature for overall survival (OS).. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of differentially expressed genes (DEGs) were performed for high- and low-risk LSCC groups. Results We identified 17 differentially expressed m7G methylation-related genes in LSCC versus normal tissues. The expression of five m7G-related genes ( EIF3D , LSM1 , NCBP2 , NUDT10 , and NUDT11 ) was identified as an independent prognostic marker for OS in LSCC patients. A risk model with these five m7G-related genes predicted 2-, and 3-year survival rates of 0.623 and 0.626, respectively. The risk score significantly correlated with OS: LSCC patients with a higher risk score had shorter OS (P<0.01) and it was associated with lower immune response (P<0.01). Conclusions We developed a novel m7G-related gene signature that can be of great utility to predict the prognosis for patients with LSCC.

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Section: Discussionmentioning

confidence: 99%

A signature of five 7-methylguanosine-related genes is a prognostic marker for lung squamous cell carcinoma

Liu,

Wang,

Ulivi

et al. 2023

J Thorac Dis

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“…The SR is controlled by the accumulation of intracellular alarmone nucleotides that are collectively known as (pp)pGpp (9, 10). These alarmones are metabolized by bifunctional synthetase/hydrolase enzymes from the RSH or Rel (RelA/SpoT homology) family, monofunctional small alarmone hydrolases (SAH), and monofunctional small alarmone synthetases (SAS) (11).…”

Section: Introductionmentioning

confidence: 99%

“…The highly conserved synthetase domains of RSH and SAS enzymes transfer a pyrophosphate from ATP to the 3’ OH of guanosine nucleotide precursors. Typically, the utilization of GMP, GDP, or GTP results in the synthesis of pGpp, ppGpp, or pppGpp, respectively (9, 10). C. difficile encodes highly conserved RSH and RelQ homologs whose alarmone synthesis contributes to antibiotic survival (10, 14, 15).…”

Section: Introductionmentioning

confidence: 99%

“…Typically, the utilization of GMP, GDP, or GTP results in the synthesis of pGpp, ppGpp, or pppGpp, respectively (9, 10). C. difficile encodes highly conserved RSH and RelQ homologs whose alarmone synthesis contributes to antibiotic survival (10, 14, 15). However, it was recently discovered that both C. difficile synthetases must hydrolyze a 5’ phosphate or pyrophosphate from their GDP or GTP substrates while transferring the ATP-derived 3’ pyrophosphate, leaving behind a 5’ monophosphate and resulting in exclusive synthesis of pGpp (10, 14, 15).…”

Section: Introductionmentioning

confidence: 99%

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RelQ-mediated alarmone signaling regulates growth, sporulation, and stress-induced biofilm formation inClostridioides difficile

Malik,

Oludiran,

Poudel

et al. 2024

Preprint

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The bacterial stringent response (SR) is a conserved transcriptional reprogramming pathway mediated by the nucleotide signaling alarmones, (pp)pGpp. The SR has been implicated in antibiotic survival in Clostridioides difficile, a biofilm- and spore-forming pathogen that causes resilient, highly recurrent C. difficile infections. The role of the SR in other processes and the effectors by which it regulates C. difficile physiology are unknown. C. difficile RelQ is a clostridial alarmone synthetase. Deletion of relQ dysregulates C. difficile growth in unstressed conditions, affects susceptibility to antibiotic and oxidative stressors, and drastically reduces biofilm formation. While wild-type C. difficile displays increased biofilm formation in the presence of sub-lethal stress, the ΔrelQ strain cannot upregulate biofilm production in response to stress. Deletion of relQ slows spore accumulation in planktonic cultures but accelerates it in biofilms. This work establishes biofilm formation and sporulation as alarmone-mediated processes in C. difficile and reveals the importance of RelQ in stress-induced biofilm regulation.

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“…The SR is controlled by the accumulation of intracellular alarmone nucleotides that are collectively known as (pp)pGpp [9,10]. These alarmones are metabolized by bifunctional synthetase/hydrolase enzymes from the RSH or Rel (RelA/SpoT homology) family, monofunctional small alarmone hydrolases (SAHs), and monofunctional small alarmone synthetases (SASs) [11].…”

Section: Introductionmentioning

confidence: 99%

RelQ-mediated alarmone signalling regulates growth, stress-induced biofilm formation and spore accumulation in Clostridioides difficile

Malik,

Oludiran,

Poudel

et al. 2024

Microbiology

Self Cite

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The bacterial stringent response (SR) is a conserved transcriptional reprogramming pathway mediated by the nucleotide signalling alarmones, (pp)pGpp. The SR has been implicated in antibiotic survival in Clostridioides difficile, a biofilm- and spore-forming pathogen that causes resilient, highly recurrent C. difficile infections. The role of the SR in other processes and the effectors by which it regulates C. difficile physiology are unknown. C. difficile RelQ is a clostridial alarmone synthetase. Deletion of relQ dysregulates C. difficile growth in unstressed conditions, affects susceptibility to antibiotic and oxidative stressors and drastically reduces biofilm formation. While wild-type C. difficile displays increased biofilm formation in the presence of sublethal stress, the ΔrelQ strain cannot upregulate biofilm production in response to stress. Deletion of relQ slows spore accumulation in planktonic cultures but accelerates it in biofilms. This work establishes biofilm formation and spore accumulation as alarmone-mediated processes in C. difficile and reveals the importance of RelQ in stress-induced biofilm regulation.

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Sound the (Smaller) Alarm: The Triphosphate Magic Spot Nucleotide pGpp

Cited by 5 publications

References 93 publications

A signature of five 7-methylguanosine-related genes is a prognostic marker for lung squamous cell carcinoma

A signature of five 7-methylguanosine-related genes is a prognostic marker for lung squamous cell carcinoma

RelQ-mediated alarmone signaling regulates growth, sporulation, and stress-induced biofilm formation inClostridioides difficile

RelQ-mediated alarmone signalling regulates growth, stress-induced biofilm formation and spore accumulation in Clostridioides difficile

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