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The eukaryotic transcriptional machinery: complexities and mechanisms unforeseen

Nature Medicine volume 9, pages 1239–1244 (2003)Cite this article

The temporal and spatial expression of specific genes is central to processes such as development, differentiation and homeostasis in eukaryotes, and is regulated primarily at the level of transcription. An understanding of the molecular basis for this regulation has presented a major challenge for the past 40 years. After early insights into genetic control mechanisms in prokaryotes, elegantly elaborated in the classic 1961 paper of Jacob and Monod, it was anticipated by many that similar principles would apply in eukaryotes. However, early studies in animal cells faced the problem of genomic complexity (including reiterated DNA sequences) and the lack of tractable genetic approaches. By the time I entered graduate school in the mid 1960s, the general RNA classes—ribosomal (rRNA), transfer (tRNA), messenger (mRNA) and the enigmatic heterogeneous nuclear (hnRNA)—had been recognized, and variations in the levels of these RNA classes were being defined during various growth, developmental, hormonal and viral responses. However, except for the early work from the laboratories of Max Birnstiel and Don Brown on the purification and structural analysis of the amplified rRNA genes of Xenopus laevis, essentially nothing was known about gene structure, transcriptional regulatory mechanisms or the basic transcriptional machinery in animal cells. Thus, the field was ripe for discovery of even the most fundamental principles of eukaryotic transcription, and a major question was how similar they would be to those of prokaryotes.

My interest in transcription was stimulated, as a Wabash College undergraduate in 1963, by a biochemistry course that covered recent work in bacterial genetic regulatory mechanisms. This interest was further heightened by a course taught by Sol Spiegelman in 1964, my first year of graduate studies in biochemistry at the University of Illinois. Although research opportunities in eukaryotic transcription were limited, I was able to join the laboratory of Bill Rutter just as he was moving to the University of Washington. Though not yet studying transcription per se, Rutter had begun a biochemical analysis of cell-specific protein synthesis during pancreatic development and had visions of extending this to the regulation of RNA synthesis. But because the pancreas was not yet amenable to transcription studies, I was forced to explore other model systems.

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Figure 1: Chromatographic resolution on Sephadex A25 of the three nuclear RNA polymerases from sea urchin embryos.
Figure 2
Figure 3: General initiation factors and PIC assembly pathways for class III genes with internal promoter elements, and activation by a gene-specific factor.
Figure 4: General initiation factors and PIC assembly pathway for class II genes with a TATA-containing core promoter, and regulation by gene-specific factors and interacting cofactors.
Figure 5: Comparison of transcription factors and activation mechanisms in prokaryotes and eukaryotes.

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Acknowledgements

I thank my mentors Bill Rutter and Don Brown for their inspiration and friendship and for the freedom to pursue my specific goals in their laboratories; my students and postdocs for their dedication and many contributions; my family for their unwavering support and understanding; and the many institutions that have supported my research over four decades.

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  1. heads the Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Ave., New York, 10021, New York, USA

    Robert G Roeder

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Roeder, R. The eukaryotic transcriptional machinery: complexities and mechanisms unforeseen. Nat Med 9, 1239–1244 (2003). https://doi.org/10.1038/nm938

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