Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling in <i>C. elegans</i>

Chi, Congwu; Ronai, Diana; Than, Minh T.; Walker, Cierra J.; Sewell, Aileen K.; Han, Min

doi:10.1101/gad.275107.115

Cited by 39 publications

(39 citation statements)

References 61 publications

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“…Our results illustrate that the holobiont metabolic complementation occurs at two levels in the context of drugs: (1) in their bioconversion and by regulating the availability of RNA-damaging fluoronucleotides such as FUTP to the host, and (2) in the supply of regulatory metabolites that synergize with 5-FU-induced DNA damage. Consistent with our observations, it was previously reported that bacterial nucleotide metabolism regulates C. elegans germline proliferation (Chi et al., 2016). …”

Section: Discussionsupporting

confidence: 93%

Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans

Scott

Quintaneiro

Norvaišas

et al. 2017

Cell

191

177

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SummaryFluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.

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Section: Discussionsupporting

confidence: 93%

Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans

Scott

Quintaneiro

Norvaišas

et al. 2017

Cell

191

177

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“…The germline of the adult animal is the most intensive user of nucleotides, so it would be logical for it to adjust cell proliferation rates accordingly with the nucleotide supply. Here, Chi et al (2016) report finding exactly such a system: Nucleotide levels provided in the worms' food source, bacteria, affect fertility through the regulation of germline proliferation via the GLP-1/NOTCH and MAPK pathways.…”

mentioning

confidence: 99%

Feeding the germline

Shi

Murphy

2016

Genes Dev.

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Nucleotides are required in order to replicate DNA in the developing germline. Here, Chi and colleagues (pp. 307-320) have used Caernohabditis elegans to identify a GLP-1-dependent checkpoint that senses food (bacterially)-supplied nucleotide levels, arresting reproductive development in the absence of sufficient nucleotide supplies.Everygrowing body needs nutrients. In fact, the need to regulate development and growth in concert with appropriate nutrient levels is so important that multiple genetic pathways-including the insulin/IGF-1, TOR, AMPK, and TGF-β signaling pathways-function primarily to report on the status of these nutrients and enforce checkpoints that prevent excessive growth in their absence.Caenorhabditis elegans is a master of survival in part because of its ability to arrest growth at multiple points in the absence of sufficient resources; the alternative third larval dauer stage is the most famous of these arrests, but L1 diapause and adult reproductive diapause (ARD) can also be induced when the animals sense that nutrient levels are too low to successfully proceed to reproduction (Cassada and Russel 1975;Johnson et al. 1984;Angelo and Van Gilst 2009). Germline proliferation is also subject to several of these regulatory checks in GLP-1/Notch-independent pathways: The insulin-like peptides INS-3 and INS-33 act nonautonomously upstream of IIS to regulate DAF-16-dependent germline proliferation (Michaelson et al. 2010); TOR (let-363), RAPTOR (daf-15), and ribosomal protein S6 kinase (rsks-1) are required in the germline autonomously to promote germline proliferation (Korta et al. 2012); and the TGF-β ligand DAF-7 relays nutrient status information from ASI sensory neurons to the TGF-β receptor (DAF-1) and co-SMAD (DAF-5) in the DTCs (distal tip cells), ultimately affecting germline proliferation (Dalfo et al. 2012).We normally think of amino acids, carbohydrates, and fats as major nutrients, and the mechanisms that regulate their sensing and intake have been well studied. However, organisms also need a source of nucleotides in order to replicate their DNA in proliferating cells. The germline of the adult animal is the most intensive user of nucleotides, so it would be logical for it to adjust cell proliferation rates accordingly with the nucleotide supply. Here, Chi et al. (2016) report finding exactly such a system: Nucleotide levels provided in the worms' food source, bacteria, affect fertility through the regulation of germline proliferation via the GLP-1/NOTCH and MAPK pathways.The investigators first found that cytidine deaminase mutants, which cannot use the pyrimidine salvage pathway to generate nucleotides, have a fertility defect that is, surprisingly, rescued by feeding with the RNAi library Escherichia coli strain HT115 rather than the standard laboratory E. coli strain (OP50). This rescue is not due to RNase III loss but rather an insertion in the cytR gene, which normally represses nucleoside uptake and metabolism, thus increasing uridine levels in the HT115 bacteria. Supplementati...

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“…In addition, we observed that in limiting‐heme conditions somatic tissues develop preferentially to the germline (Table , Figs and ). This resembles the arrest in germline proliferation observed when C. elegans is provided with inadequate levels of uridine/thymidine . The latter is regulated by the Glp‐1/Notch and MPK‐1/MAPK pathways, and suggests the existence of a previously unknown mechanism for sensing nucleotide levels in the germline.…”

Section: Discussionmentioning

confidence: 62%

The heme auxotroph Caenorhabditis elegans can cleave the thioether bonds of c‐type cytochromes

et al. 2018

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Heme is essential and synthesized via highly regulated processes. For this reason, most organisms strive to recycle it or acquire it from their environment. When heme is bound to proteins noncovalently, degradation of the polypeptide is sufficient to release it. However, in some hemoproteins, such as c-type cytochromes, heme is covalently bound to the protein backbone. We use the heme auxotroph Caenorhabditis elegans to investigate if cytochromes c can be a heme source, and we show that this organism must encode a novel system which specifically cleaves the thioether bonds of c-type cytochromes. We also find that at limiting heme concentrations, while somatic tissues develop normally the germline fails to proliferate, suggesting the presence of a heme-sensing checkpoint in C. elegans.

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Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling in C. elegans

Cited by 39 publications

References 61 publications

Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans

Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans

Feeding the germline

The heme auxotroph Caenorhabditis elegans can cleave the thioether bonds of c‐type cytochromes

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