Function and regulation of the Mediator complex

Abstract

Over the past few years, advances in biochemical and genetic studies of the structure and function of the Mediator complex have shed new light on its subunit architecture and its mechanism of action in transcription by RNA polymerase II (pol II). The development of improved methods for reconstitution of recombinant Mediator subassemblies is enabling more in-depth analyses of basic features of the mechanisms by which Mediator interacts with and controls the activity of pol II and the general initiation factors. The discovery and characterization of multiple, functionally distinct forms of Mediator characterized by the presence or absence of the Cdk8 kinase module have led to new insights into how Mediator functions in both Pol II transcription activation and repression. Finally, progress in studies of the mechanisms by which the transcriptional activation domains (ADs) of DNA binding transcription factors target Mediator have brought to light unexpected complexities in the way Mediator participates in signal transduction.

Fig. 1. Multiple Forms of Mediator

Biochemical and EM structural studies have revealed that Mediator is present in cells in at least three forms: a Mediator core, which is composed of more than twenty subunits arranged in three modules referred to as head, middle, and tail; a holoenzyme, in which the Mediator core adopts a more open conformation that encircles and binds tightly to pol II; and a third form, in which the kinase module binds to the Mediator core in a manner that precludes Mediator binding to pol II. Understanding molecular mechanisms by which each form of Mediator contributes to transcriptional activation and repression, as well as the biochemical pathways leading to the assembly and possible interconversion of the different forms of Mediator, are key challenges for future investigations of the role Mediator plays in regulating gene expression.