Mechanisms and Developmental Roles of Promoter-proximal Pausing of RNA Polymerase II.

Christine Robinson,Matthew Lowe

doi:10.4172/2157-7633.1000330

Abstract

RNA polymerase II (Pol II) temporarily stops transcription after synthesizing 30–50 bases, and resumes elongation only after stimulations by various signaling molecules and developmental cues. This phenomenon, called promoter-proximal pausing, is observed in 10–50% of the entire genes from Drosophila embryos to human cells. Release of paused Pol II is primarily mediated by the activated form of positive transcription elongation factor b (P-TEFb) initially sequestered in the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP) complex. Many proteins and RNAs have been discovered and studied in detail to explain the process of the pausing and release of Pol II in relation to P-TEFb. At the functional level, promoter-proximal pausing regulates genes involved in stimulus-response and development in Drosophila. In mammalian stem cell biology, pausing is important for proliferation and signaling in embryonic stem cells and the formation of induced pluripotent stem cells. Other than this, however, little is known about the biological significance of pausing in mammalian cell differentiation. Further study on pausing mechanisms as well as its functions will contribute to the development of stem cell biology and its clinical applications.

Highlights

After RNA polymerase II (Pol II) and general transcription factors are assembled to form the pre-initiation complex (PIC) at a promoter, it synthesizes a short mRNA of 30-50 bases and pauses [1,2,3,4,5,6] (Figure 1A)
The PIC is directly inhibited by two protein complexes: 5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) sensitivity-inducing factor (DSIF, containing Supt4a and Supt5) and negative elongation factor (NELF, composed of subunits A-E)
The 3’ untranslated region (UTR) of human I-mfa domain containing protein (HIC) mRNA is necessary and sufficient to activate gene expression at the human immunodeficiency virus (HIV)-1 promoter by displacing 7SK RNA from positive transcription elongation factor b (P-TEFb), allowing it to dissociate from 7SK 7SK Small Nuclear Ribonucleoprotein (snRNP) [20]

Summary

Introduction

After RNA polymerase II (Pol II) and general transcription factors are assembled to form the pre-initiation complex (PIC) at a promoter, it synthesizes a short mRNA of 30-50 bases and pauses (promoter-proximal pausing or PPP) [1,2,3,4,5,6] (Figure 1A). The 3’ untranslated region (UTR) of HIC mRNA is necessary and sufficient to activate gene expression at the HIV-1 promoter by displacing 7SK RNA from P-TEFb, allowing it to dissociate from 7SK snRNP [20].

Results

Conclusion