Activation and Repression of Transcription by Differential Contact: Two Sides of a Coin

Abstract

Activation and repression of transcription are primarily caused by gene regulatory proteins (activators and repressors), which act by binding to specific sites on DNA. The steps from initial binding of RNA polymerase to the elongating complex are characterized by many intermediates, each with a discrete structure, offering many mechanistic possibilities for regulator actions. It has been shown in some systems that the activator acts by helping RNA polymerase or other associated factors to bind (recruitment) and/or by influencing a postrecruitment step (isomerization, promoter clearance, etc.) (1-7). We have used the term recruitment for referring to assistance only on the initial binding step of RNA polymerase. We caution that a postbinding step may be indistinguishable from the recruitment step if they are in rapid equilibrium. Clearly, all activators do not act at the level of RNA polymerase recruitment to the promoters. There are activators demonstrated to help postbinding steps that have no effect on initial binding (4-7). Promoter-specific repression can occur by sterically hindering the binding of RNA polymerase or of, in principle, another essential transcription factor to the promoter (8, 9). However, other studies in several promoters, as was anticipated (10), point toward repressor action also through contact with promoter-bound RNA polymerase at a postbinding step (11-17). More interestingly, some regulators act as activator in one context and as repressor in another (13, 15). Although the contact regions on the surface of some regulators and of RNA polymerase have been mapped (18, 19), how these contacts cause activation or inhibition of transcription initiation in biochemical terms is not known. In principle, the contact may affect the process of transcription initiation (i) by allosteric modification of RNA polymerase and/or (ii) by energetic stabilization of an intermediate(s). Regulator-induced conformation changes in RNA polymerase by protein-protein contact may contribute to the regulation process. However, a regulator-RNA polymerase contact may play a fundamentally different role in transcription initiation. In this article, we provide a conceptual framework for the process of activator and repressor action through differential stabilization of one or more of the intermediate states of RNA polymerase-promoter complex by its contact with the regulator. We portray regulators as catalysts. From a thermodynamic point, we view that activators, like catalysts, lower the activation energy of some step(s) in the reaction pathway of transcription initiation. As discussed below, a similar energetic argument explains the action of repressors. To make our point, we discuss simple examples of DNA-binding regulators modulating RNA polymerase during transcription initiation in selected prokaryotic systems.