Robert G. Roeder

Robert G. Roeder has revealed the principle of the regulatory mechanism of transcription in eukaryotes through his over 50 years of transcriptional research, by identifying functions of a series of factors such as three distinct RNA polymerases, basic transcription factors, one of the first gene-specific factors, and regulators in transcription from chromatin. Through his achievements, he has made significant contributions to develop present life science.

＊This field then was Field of Life Sciences (Molecular Biology, Cell Biology, Neurobiology).

Robert G. Roeder has identified in animal cells a series of factors involved in the initiation of transcription from DNA to RNA and has revealed their functions. He elucidated the principle of gene expression mechanisms in eukaryotes and laid the foundation for current life sciences.

Using a “cell-free reconstitution system” which reproduces transcription reaction in vitro, in 1969, Roeder first identified three distinct RNA polymerases designated as Pols I, II, and III in eukaryotes (1), and by 1974, discovered that Pol I transcribes precursor RNAs such as those for 28S, 18S, and 5.8S ribosomal RNA (rRNA); Pol II transcribes precursor mRNA; and Pol III transcribes 5S rRNA and tRNA (2, 3). He further purified each RNA polymerase, combined each with various fractions of nuclear extracts in the reconstitution assays, and revealed that transcription is initiated by multiprotein complexes called preinitiation complexes (PICs), formed by each RNA polymerase with general transcription initiation factors. These PICs bind to DNA sequences called promoters near the transcription initiation sites (4–9).

In addition to the general transcription factors, eukaryotes require gene-specific transcription factors that direct transcriptional activation of a specific gene or a specific set of genes in response to environmental changes. Roeder identified TFIIIA as a gene-specific transcription factor for the 5S rRNA gene and revealed that TFIIIA recruits Pol III and its PIC to the promoter of 5S rRNA gene and activates its transcription (10, 11). This was a pioneering work to elucidate the function of gene-specific transcription factors. Since then, hundreds of specific transcription factors have been identified. Roeder then revealed that a multiprotein complex called the mediator bridges gene-specific transcription factors on a distal enhancer and general transcriptional machinery on a promoter to facilitate their physical and functional interaction for transcription initiation of the target gene (12, 13).

In eukaryotes, DNA wraps around histone octamer, forming nucleosomes that make up the chromatin. Roeder further extended his study to examine the transcription mechanism from chromatin DNA. He discovered that binding of the activator-driven PIC to the promoter occurs in a mutually exclusive manner with nucleosome assembly (14, 15), and further showed in the reconstitution system that modification of the histone N-terminal tails was indispensable for transcription of chromatin DNA (16). These studies of Roeder culminated in 2006 in the reconstruction of a machinery of more than 80 polypeptides that initiates and elongates transcription from inactive chromatin (17).

Roeder, who has devoted his life to transcription research for over 50 years with ceaseless efforts, has thus discovered the RNA polymerases, the general transcription factors, the prototype of gene-specific factors and their functions, and mechanisms of transcription from chromatin, thus elucidating the principle of transcription mechanisms in eukaryotes and making outstanding contributions to the development of life sciences.

For these reasons, the Inamori Foundation is pleased to present the 2021 Kyoto Prize in Basic Sciences to Robert G. Roeder.

References
(1) Roeder RG & Rutter WJ (1969) Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms. Nature 224: 234–237.
(2) Weinmann R & Roeder RG (1974) Role of DNA-dependent RNA polymerase III in the transcription of the tRNA and 5S RNA genes. Proc Natl Acad Sci U S A 71: 1790–1794.
(3) Weinmann R, Raskas HJ & Roeder RG. (1974) Role of DNA-dependent RNA polymerases II and III in transcription of the adenovirus genome late in productive infection. Proc Natl Acad Sci U S A 71: 3426–3439.
(4) Sklar VE et al. (1975) Distinct molecular structures of nuclear class I, II, and III DNA-dependent RNA polymerases. Proc Natl Acad Sci U S A 72: 348–352.
(5) Parker CS & Roeder RG (1977) Selective and accurate transcription of the Xenopus laevis 5S RNA genes in isolated chromatin by purified RNA polymerase III. Proc Natl Acad Sci U S A 74: 44–48.
(6) Weil PA et al. (1979) Selective and accurate initiation of transcription at the Ad2 major late promotor in a soluble system dependent on purified RNA polymerase II and DNA. Cell 18: 469–484.
(7) Matsui T et al. (1980) Multiple factors required for accurate initiation of transcription by purified RNA polymerase II. J Biol Chem 255: 11992–11996.
(8) Lassar AB et al. (1983) Transcription of class III genes: formation of preinitiation complexes. Science 222: 740–748.
(9) Horikoshi M et al. (1989) Cloning and structure of a yeast gene encoding a general transcription initiation factor TFIID that binds to the TATA box. Nature 341: 299–303.
(10) Engelke DR et al. (1980) Specific interaction of a purified transcription factor with an internal control region of 5S RNA genes. Cell 19: 717–728.
(11) Ginsberg AM et al. (1984) Xenopus 5S gene transcription factor, TFIIIA: characterization of a cDNA clone and measurement of RNA levels throughout development. Cell 39: 479–489.
(12) Meisterernst M et al. (1991) Activation of class II gene transcription by regulatory factors is potentiated by a novel activity. Cell 66: 981–993.
(13) Ito M et al. (1999) Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators. Mol Cell 3: 361–370.
(14) Workman JL & Roeder RG (1987) Binding of transcription factor TFIID to the major late promoter during in vitro nucleosome assembly potentiates subsequent initiation by RNA polymerase II. Cell 51: 613–622.
(15) Workman JL et al. (1988) Transcriptional regulation by the immediate early protein of pseudorabies virus during in vitro nucleosome assembly. Cell 55: 211–219.
(16) An W et al. (2002) Selective requirements for histone H3 and H4 N termini in p300-dependent transcriptional activation from chromatin. Mol. Cell 9: 811–821.
(17) Guermah M et al. (2006) Synergistic functions of SII and p300 in productive activator-dependent transcription of chromatin templates. Cell 125: 275–286.