50+ years of eukaryotic transcription: an expanding universe of factors and mechanisms

Abstract

The landmark 1969 discovery of nuclear RNA polymerases I, II and III in diverse eukaryotes represented a major turning point in the field that, with subsequent elucidation of the distinct structures and functions of these enzymes, catalyzed an avalanche of further studies. In this Review, written from a personal and historical perspective, I highlight foundational biochemical studies that led to the discovery of an expanding universe of the components of the transcriptional and regulatory machineries, and a parallel complexity in gene-specific mechanisms that continue to be explored to the present day.

Fig. 1 |. General initiation factors and PIC assembly pathways for Pol III-transcribed genes with internal promoter elements, and activation by a gene-specific activator.

On the tRNA gene (left), assembly of a functional PIC containing Pol III and general initiation factors (yellow) is nucleated by stable binding of TFIIIC to the Box A and Box B elements. In contrast, assembly of a PIC on the divergent promoter of the 5S RNA gene is more highly regulated and requires prior binding to Box A and Box C of the 5S RNA gene-specific transcriptional activator TFIIIA, which interacts with and stabilizes TFIIIC binding. For both genes, TFIIIB is recruited by TFIIIC and Pol III is recruited by TFIIIB and TFIIIC. Solid black bars indicate interactions between Pol III and the various factors, NTP, ribonucleoside triphosphates. Adapted from ref..

Fig. 2 |. General initiation factors and PIC assembly pathway for a Pol II-transcribed gene with a strong TATA-containing core promoter, and regulation by gene-specific factors and interacting cofactors.

Assembly of a PIC containing Pol II and general initiation factors (yellow) is nucleated by binding of TFIID to the TATA element of the core promoter. A model for the regulation of PIC assembly and function involves, sequentially: (i) binding of regulatory factors to distal control elements; (ii) regulatory factor interactions with cofactors that modify chromatin structure to facilitate additional factor interactions; and (iii) regulatory factor interactions with cofactors that act after chromatin remodeling to facilitate, through direct interactions, recruitment or function of components the general transcription machinery. Solid black bars indicate direct interactions between the indicated factors. TAFs, TBP-associated factors. AD, activation domain. DBD, DNA binding domain. TSS, transcription start site. Adapted from ref..