We continue to focus on transcription regulation by (p)ppGpp in eubacteria. Negative regulation by (p)ppGpp appears to occur by a fundamentally different mechanism than for positive regulation. Negative regulation by (p)ppGpp is well studied. It is unusual because it does not involve recruitment of RNA polymerase (RNAP) by DNA binding proteins that bind operators through recognition of specific sequences. Instead (p)ppGpp binds RNAP synergistically with a protein (DksA) containing a coiled-coil finger that inserts into the secondary (substrate) channel of RNAP. This co-binding event probably alters RNAP conformation which, in turn, directly alters gene-specific transcription initiation kinetics for different classes of promoters depending on their sequence. Other secondary channel proteins with similar structures can elicit similar effects without (p)ppGpp. The focus is now on positive regulation by (p)ppGpp, which is poorly understood. The sequences of these promoters fall into two distinct classes: host anabolic housekeeping genes and pathogenicity island virulence genes. Neither sequence class allows a simple explanation for regulation based on prior knowledge of negative regulation. Studies of (p)ppGpp dependence of threonine operon expression suggest regulation is exerted on a transcription step downstream of promoter activation itself. Deductions from sequences of virulence gene promoters also suggest new, but different mechanisms for induction by (p)ppGpp.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
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
Bruhn-Olszewska, Bo?ena; Molodtsov, Vadim; Sobala, Micha? et al. (2018) Structure-function comparisons of (p)ppApp vs (p)ppGpp for Escherichia coli RNA polymerase binding sites and for rrnB P1 promoter regulatory responses in vitro. Biochim Biophys Acta Gene Regul Mech 1861:731-742
Kamarthapu, Venu; Epshtein, Vitaly; Benjamin, Bradley et al. (2016) ppGpp couples transcription to DNA repair in E. coli. Science 352:993-6
Gaca, Anthony O; Kudrin, Pavel; Colomer-Winter, Cristina et al. (2015) From (p)ppGpp to (pp)pGpp: Characterization of Regulatory Effects of pGpp Synthesized by the Small Alarmone Synthetase of Enterococcus faecalis. J Bacteriol 197:2908-19
Mechold, Undine; Potrykus, Katarzyna; Murphy, Helen et al. (2013) Differential regulation by ppGpp versus pppGpp in Escherichia coli. Nucleic Acids Res 41:6175-89
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
Edwards, Adrianne N; Patterson-Fortin, Laura M; Vakulskas, Christopher A et al. (2011) Circuitry linking the Csr and stringent response global regulatory systems. Mol Microbiol 80:1561-80
James, Tamara D; Cashel, Michael; Hinton, Deborah M (2010) A mutation within the {beta} subunit of Escherichia coli RNA polymerase impairs transcription from bacteriophage T4 middle promoters. J Bacteriol :

Showing the most recent 10 out of 15 publications