Robert G. Roeder
2021 Kyoto Prize Laureates
Life Sciences（Molecular Biology, Cell Biology, Neurobiology）
/ Biochemist and Molecular Biologist
Arnold and Mabel Beckman Professor of Biochemistry and Molecular Biology, The Rockefeller University
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.
All the cells in our body have the same set of genetic information; yet, they differentiate to have various morphologies and functions, respond uniquely to changes in internal and external environments, and work together to enable our activities as living individuals. Such cellular differentiation and responses, characteristic of eukaryotes, are primarily achieved through the transcription of a combination of genes specific to each cell. Robert G. Roeder identified in animal cells a series of transcription factors generally involved in the initiation of transcription from DNA to RNA, and the first example of specific transcription factors that interact with these general transcription factors to initiate transcription of a specific gene. By revealing their functions, he elucidated the principle of gene expression mechanisms in eukaryotes and laid the foundation for current life sciences.
A distinguishing feature of his research was to use a “cell-free reconstitution system” in which he added various components and reproduced transcription from DNA to RNA in vitro. Using this system, in 1969, he first identified three distinct RNA polymerases designated as I, II, and III in eukaryotes (1), and by 1974, discovered that RNA polymerase I (Pol I) transcribes precursor RNAs involved in protein synthesis, such as those for 28S, 18S, and 5.8S ribosomal RNA (rRNA); RNA polymerase II (Pol II) transcribes precursor mRNA that codes for amino acid sequences of proteins; and RNA polymerase III (Pol III) transcribes 5S rRNA and tRNA (2, 3). He further purified each RNA polymerase, combined it with various fractions of nuclear extracts in the reconstitution assays, and revealed that transcription cannot be initiated by RNA polymerase alone, but by multiprotein complexes, formed by each RNA polymerase with general transcription initiation factors, called preinitiation complexes (PICs). These PICs bind to DNA sequences called promoters near the transcription initiation sites (4-9). It is now known that Pol I, Pol II, and Pol III require 9, 32, and 6 general transcription factors for transcription initiation, respectively.
In addition to the above stated 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. Many of these gene-specific transcription factors recognize sequences called enhancers, which are often located far from the promoter in the genome. In mammalian cells, Roeder revealed that a multiprotein complex called the mediator bridges gene-specific transcription factors on a remote 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 basic proteins called histones, forming nucleosomes that make up the chromatin. Roeder further extended his study to examine the transcription mechanism of chromatin DNA by introducing nucleosome assembly into the cell-free system. He first discovered that binding of the activator-driven PIC to the promoter occurs in a mutually exclusive manner with nucleosome assembly (14, 15), and then showed in his cell-free system reconstituted with recombinant histones and coactivators that modification of the histone N-terminal tails was indispensable for transcription of chromatin DNA (16). These studies have significantly contributed to our understanding of the epigenetic regulation of transcriptional initiation. These studies of Roeder culminated in 2006 in the reconstruction of a machinery of more than 80 polypeptides that initiate and elongate transcription from inactive chromatin (17).
Roeder has thus elucidated the principle of transcription mechanisms in eukaryotes and made outstanding contributions to the development of life sciences. Roeder has devoted his life to transcription research for over 50 years, and thus deserves the Kyoto Prize in Basic Sciences that recognizes ceaseless efforts to study the secrets of nature.
(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.
Profile is at the time of the award.