Elongation by RNA polymerase II: the short and long of it

Abstract

Appreciable advances into the process of transcript elongation by RNA polymerase II (RNAP II) have identified this stage as a dynamic and highly regulated step of the transcription cycle. Here, we discuss the many factors that regulate the elongation stage of transcription. Our discussion includes the classical elongation factors that modulate the activity of RNAP II, and the more recently identified factors that facilitate elongation on chromatin templates. Additionally, we discuss the factors that associate with RNAP II, but do not modulate its catalytic activity. Elongation is highlighted as a central process that coordinates multiple stages in mRNA biogenesis and maturation.The regulation of gene expression is one of the most intensely studied areas in all of science. Differential gene expression in multicellular organisms forms the foundation of cell-type specificity. Deregulation of the appropriate pattern of gene expression has profound effects on cellular function and underlies many diseases. Although there are many cellular processes that control gene expression, the most direct regulation occurs during transcription. The transcription of protein-coding genes in eukaryotes is performed by RNA polymerase II (RNAP II). Up until recently, the vast majority of studies aimed at elucidating the molecular mechanisms of transcription regulation have focused on early stages, such as the formation of a transcription initiation complex (preinitiation) and initiation (see below). For many years, transcript elongation has been thought of as the trivial addition of ribonucleoside triphosphates to the growing mRNA chain. It is now apparent that this process is a dynamic and highly regulated stage of the transcription cycle capable of coordinating downstream events. Numerous factors have been identified that specifically target the elongation stage of transcription. Importantly, multiple steps in mRNA maturation, including premRNA capping, splicing, 3Ј-end processing, surveillance, and export, are modulated through interactions with the RNAP II transcript elongation complex (TEC). It also appears that distinct elongation factors function in specific transcriptional contexts; the requirements for these specialized factors are largely unknown and highlight the need to better understand elongation in vivo. Many molecular and biochemical approaches have been used to quantify the different aspects of elongation, many of which are discussed below. It remains important to assimilate both in vitro and in vivo experimental systems when discussing what constitutes an elongation factor. An elongation factor can be defined as any molecule that affects the activities of or is associated with the TEC. We suggest that there are at least two major types of transcript elongation factors: one family, referred to as active elongation factors, and a second family, denoted as passive elongation factors. The difference resides in whether the factor affects the catalytic activity of RNAP II, regardless of whether the factor remains associate...

Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A

“…[2][3][4] We therefore generated mice lacking one of these factors, Elongin A. Elongin A À/À embryos were severely retarded in development and died between days 10.5 and 12.5 of gestation, most likely owing to extensive apoptosis. Moreover, MEFs derived from Elongin A À/À embryos exhibited not only increased apoptosis but also senescence-like growth defects, accompanied by the activation of p38 MAPK and p53.…”

“…1 In addition, a diverse collection of elongation factors that promote efficient elongation of transcripts by pol II in vitro have also been identified. [2][3][4] These factors fall into two broad functional classes based on their ability to either reactivate arrested pol II or suppress the transient pausing of pol II. The first class is composed of members of the SII family.…”

Transcriptional activators and activation mechanisms

“…It has been suggested that promoters with preloaded RNAP can respond to activation signals more "quickly" and uniformly (Boettiger and Levine, 2009). In addition, paused RNAP has been suggested to provide a checkpoint to ensure a successful coupling between transcription and mRNA processing or to prevent "mistakes" during the transcription process (Sims et al, 2004a;Levine, 2011).…”

“…Many proteins (or complexes) have been identified that play important roles in facilitating transcription elongation, and some of these factors represent targets for activators (Sims et al, 2004a;Peterlin and Price, 2006). For example, experiments in Drosophila suggested that the elongation factor P-TEFb is recruited to the heat shock loci to facilitate transcription elongation upon heat shock induction (Lis et al, 2000).…”

Deregulated expression of pro-survival and pro-apoptotic p53-dependent genes upon Elongator deficiency in colon cancer cells

“…Whereas pre-initiation and initiation steps of transcription involve multiple levels of regulation, there are now accumulating evidences for transcriptional elongation being a tightly regulated process that requires a plethora of proteins, for example the elongation factors [21] such as TFIIF, TFIIH, and the multi-protein complex FACT [22]. In this context, gene transcription in response to DNA-damaging agents relies on gene-and signal-specific elongation factors [23].…”