Integration Of Macromolecular Synthesis

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

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.