Two naturally occurring nucleotides, abbreviated as (p)ppGpp, are the long term focus of our lab. These are analogs of GTP and GDP with 3'- pyrophosphate residues that function as important second messengers in bacteria, plants and now arguably in animal cells, including humans. It is well known that nutritional stress signals increase (p)ppGpp to provoke either positive or negative regulation of global gene expression at the transcriptional level in bacteria and plants. Recently another lab discovered genes encoding (p)ppGpp-specific hydrolases, called Mesh 1 in worms, flies and humans (Sun et al., Nature Struct. Mol. Biol. 17:1188-94, 2010). Recent genomic analyses are confirmatory (Atkinson et al., PLoS One 6(8), e23479. 2011). These enzymes are close structural and catalytic mimics of their bacterial counterparts. While it is technically difficult to demonstrate (p)ppGpp itself in animal cells, these observations seem likely to reverse a long held view that (p)ppGpp is limited to bacteria and plant organelles that have evolved from bacteria. This is because genetic studies with Drosophila reveal animal and bacterial genes in (p)ppGpp metabolism function interchangeably, like plant genes. For example, excess (p)ppGpp made in flies by a bacterial synthetase enzyme perturbs embryogenesis with a phenotype similar to what is seen with a deletion of the Mesh1 (p)ppGpp hydrolase gene. Also transcriptional profiles of global regulatory effects of excess (p)ppGpp in flies are reminiscent of similar effects in bacteria. Our research now has a new and exciting goal in addition to continue to define molecular details of (p)ppGpp regulation in bacteria. The new goal is to identify the putative eukaryotic (p)ppGpp synthetase whose existence is implied by the presence of Mesh1 hydrolase or to otherwise account for the hydrolase. The other goal is to continue to define molecular details of (p)ppGpp regulation in bacteria.

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Molodtsov, Vadim; Sineva, Elena; Zhang, Lu et al. (2018) Allosteric Effector ppGpp Potentiates the Inhibition of Transcript Initiation by DksA. Mol Cell 69:828-839.e5
Potrykus, Katarzyna; Cashel, Michael (2018) Growth at best and worst of times. Nat Microbiol 3:862-863
Fernández-Coll, Llorenç; Cashel, Michael (2018) Contributions of SpoT Hydrolase, SpoT Synthetase, and RelA Synthetase to Carbon Source Diauxic Growth Transitions in Escherichia coli. Front Microbiol 9:1802
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Vinella, Daniel; Potrykus, Katarzyna; Murphy, Helen et al. (2012) Effects on growth by changes of the balance between GreA, GreB, and DksA suggest mutual competition and functional redundancy in Escherichia coli. J Bacteriol 194:261-73
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