RNA Polymerases as Molecular Machines

Dear Colleagues,

Transcription is the first step of gene expression, which is catalyzed by RNA polymerases through three sequential stages: transcription initiation, elongation and termination. Although cellular RNA polymerases carry at the core of their structures only the plain activity that catalyzes successively formation of phosphodiester bonds, a network of proteins and protein-ribonucleic acid complexes impinge on the polymerases and impart high-order functions of great complexity. These regulatory factors are able to interact with a cognate RNA polymerase to form high-order structures each responsible for a specific stage or step through the transcription cycle. It is a wonder how massive and complicated these structures can be and how precisely specific their functions are defined. For instance, RNA polymerase II (Pol II, 12-subunit with M.W. of 513 KDa) assembles with five general (or basal) transcription factors onto core regions of Pol II-specific promoters to form the pre-initiation complex (PIC, 31-subunit with M.W. > 1 MDa) with a precise biochemical and structural definition. The Pol II structure then varies as driven by the ATP hydrolysis and initial phosphodiester-bond formation during transcription initiation, and escapes into the early elongation complex in which elongation factors are bound while the initiation factors have dissociated. Factor exchange and conformation remodeling events also occur once Pol II has read polyadenylation and termination sequences and cause the polymerase to disengage from a template DNA. As such, RNA polymerase systems have been viewed as protein machines equipped with molecular devices capable of tuning the activities with great intricacy. In eukaryotic systems, yet additional complexity and layers of regulation are attained from the organization of genomic DNA. Nuclear DNAs wrap around the heteromeric histone octomer to assemble the compact nucleosome core particle, and with the aid of linker histone, nucleosomes further organize into high-order chromatin structures that are much more compact and resistant to transcription. To large degrees, the interplay between RNA polymerase machineries and chromatin structures is what determines the activity state of a eukaryotic genome. Biochemical and structural studies over the past two decades have uncovered many details about the structure-and-function relationships that regulate cellular RNA polymerase machines. Take again the Pol II machinery for instance, the PIC is regulated within the much larger holo-Pol II complex that also includes the Mediator complex, and the conformation of Mediator appears to shift according to what DNA sequence-specific activator is involved, thus generating gene-specificity. Pol II molecules that escape from the promoter-centered PIC then become subject to actions from elongation factors which can be either stimulatory or inhibitory, and also responsive to signaling pathways. The transition from initiation at the promoter to early elongation proximal to the promoter is a major window of regulation for especially responsive genes such as those involved in cell development. Throughout the early-elongation and next phase, which is the productive elongation of RNA chain, the polymerase directly and indirectly interacts with yet other diverse proteins, and the new Pol II complexes thus formed obligate active transcriptions to RNA processing (e.g. 5’ capping and splicing) events and chromatin-modifying activities (e.g. histone methylation). Finally as Pol II approaches the 3’-end of an open-reading frame, it recruits the 3’ processing and polyadenylation machinery onto the elongation complex to induce transcript cleavage, addition of an adenosine string to RNA 3’ end, and termination of transcription. Pol II molecules that have disengaged from DNA templates rapidly receive a posttranslational modification that returns the polymerases to the state suitable for another round of initiation. The control of polymerase activities throughout these stages of the transcription cycle requires temporal and spatial coordination among the diverse groups of factors involved in the machinery. A large part of the current research effort in the field is directed at elucidating the biochemical and structural details that underlie the processes. The purpose of this special issue of Molecules is to highlight mechanistic understandings gained from recent studies of various RNA polymerase machineries, with a particular viewpoint of structure-and-function relationship.

Dr. Jianhua Fu
Guest Editor

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