2006 kornberg_lecture

2006 kornberg_lecture - The molecular basis of eukaryoTic...

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176 THE MOLECULAR BASIS OF EUKARYOTIC TRANSCRIPTION Nobel Lecture, December 8, 2006 by R oger D. K ornberg Stanford University, School of Medicin, Fairchild D 123, Stanford, CA 94305-5126, USA. I am deeply grateful for the honor bestowed on me by the Nobel Committee for Chemistry and the Royal Swedish Academy of Sciences. It is an honor I share with my collaborators. It is also recognition of the many who have con- tributed over the past quarter century to the study of transcription. THE NUCLEOSOME My own involvement in studies of transcription began with the dis- covery of the nucleosome, the basic unit of DNA coiling in eukaryote chromosomes [1]. X-ray studies and protein chemistry led me to propose the wrapping of DNA around a set of eight histone molecules in the nucleosome (Fig. 1). Some years later, Yahli Lorch and I found this wrapping of DNA prevents the ini- tiation of transcription in vitro [2]. Michael Grunstein and colleagues showed nucleosomes interfere with transcription in vivo [3]. The nuc- leosome serves as a general gene repressor. It assures the inactivity of all the many thousands of genes in eukaryotic cells except those whose transcription is brought about by specific positive regulatory mechanisms. What are these posi- tive regulatory mechanisms? How is repression by the nucleosome over- come for transcription? Our recent Figure 1. The nucleosome, fundamental particle of the eukaryote chromosome. Schematic shows the coiling of DNA around a set of eight histones in the nucleosome, the further coiling in condensed (transcrip- tionally inactive) chromatin, and uncoiling for interaction with the RNA polymerase II (pol II) transcription machinery.
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177 work has shown that promoter chromatin is transformed from a static to a dynamic state upon gene activation [4]. Nucleosomes are rapidly removed and reassembled in the activated state. Promoter DNA is made transiently available for interaction with the transcription machinery. RNA POLYMERASE II TRANSCRIPTION Our studies have focused on the RNA polymerase II (pol II) transcription machinery. Pol II is responsible for all messenger RNA synthesis in eukary- otes. As the first step in gene expression, pol II transcription is an end point of a great many signal transduction pathways. The intricate regulation of pol II transcription underlies cell differentiation and development. Because nucleosomes are removed from promoter DNA for transcription in vivo , we and others have been able to fractionate the components of the transcription machinery guided by transcription assays performed with naked DNA in vitro . Robert Roeder and colleagues initiated the isolation of pol II transcription proteins from human HeLa cell extracts [5]. This effort was brought to fruition by Ronald and Joan Conaway, who took advantage of the greater abundance of starting material available from a rat liver extract [6]. We at Stanford isolated the pol II machinery from yeast, in work begun by
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2006 kornberg_lecture - The molecular basis of eukaryoTic...

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