Kornberg wins Nobel Prize in Chemistry

The 2006 Nobel Prize in Chemistry has been awarded to Roger Kornberg, professor of structural biology at the Stanford University School of Medicine. The Nobel Foundation honors his 2001 papers showing the crystal structure of RNA Polymerase II at atomic resolution, which greatly improved the understanding of eukaryotic transcription. The award marks the second Nobel Prize to be given this week to researchers focused on RNA, as well as the second to go to a Stanford researcher. On Monday, Andrew Z. Fire, professor in Stanford's Department of Pathology and Genetics, and Craig C. Mello, professor of Molecular Medicine at the University of Massachusetts Medical School, won the prize in physiology or medicine for uncovering the mechanism of RNA interference."Unlike the prize earlier this week for RNA interference, which was really a discovery, [Kornberg's work] is a case where it took decades of persistent work and developing methods along the way to make the progress that he has," Jeremy Berg, director of the National Institute of General Medical Science, told The Scientist.Peter Fraser, of the Babraham Institute in Cambridge, also emphasized that Kornberg's crystallization work was the result of a long and productive career. "They are awarding the prize for the work he's done on the crystallization of the RNA polymerase complex? but he has spent years building up to that," he said. In fact, Kornberg's path to the Nobel Prize could be said to have begun when he was only a child. At the age of 12, he attended the 1959 Nobel award ceremony where his father, Arthur Kornberg, was awarded the physiology or medicine prize.Almost two decades later, Kornberg was carving out his own scientific niche as a post-doctoral student at the Medical Research Council in Cambridge, where he worked beside Francis Crick and Aaron Klug. There, in 1974, Kornberg first described nucleosomes, the repeated unit of packed DNA. But his finding was met with a lukewarm response. Scientists accepted that DNA was packaged as chromatin, said Berg, "but it [chromatin] wasn't regarded as having a real role in gene regulation." Since then, scientists have discovered that DNA packaging plays a vital role in regulating gene expression.Starting his own lab at Stanford, Kornberg continued to study the mechanism of transcription, but he turned his attention to the RNA polymerase complex. "At the time, this was incredibly ambitious," said Berg "and it wasn't the least bit clear how to get from what we knew to what we wanted to know." By 1987, Kornberg had developed a system to reconstitute S. cerevisae transcription in vitro. But these reconstituted systems were not being stimulated by transcriptional activators. In looking for the missing link, Kornberg discovered Mediator, a large protein complex now considered a critical part of regulated transcription.As the biochemical pieces were starting to form a comprehensible picture, the structural and chemical aspects of transcription were still far from clear. It wasn't until Kornberg published his 2001 crystallography papers - which both appeared in the same issue of Science -- that the field could begin to grasp the chemical mechanism of gene transcription. One paper showed the crystal structure of 10 RNA polymerase subunits at a resolution of 2.8 Angstroms. The authors identified four mobile modules, one of which acts a clamp to hold DNA promoter regions for transcription initiation. The study also used a Fourier map showing that the active site carries two metal ions and suggested a possible exit strategy for the newly synthesized RNA.The other paper addressed the 3.3 Angstrom crystal structure of RNA polymerase as it is transcribing a gene. This structure shows how the double-stranded DNA enters the enzyme and is unwound adjacent to the active site. It also reveals the DNA-RNA hybrid structure and the pores where nucleotides can enter the complex. In addition, Kornberg was able to identify the RNA exit site. Throughout his career, Kornberg has maintained a relatively small lab, with about 20 active lab members. "It's not like those American empire labs with 30 or 40 postdocs," said Jesper Svejstrup, a former post-doc in Kornberg's lab who is now a principal investigator at Cancer Research UK. "Especially in the beginning, he would know more and remember more about my project than I did. It was very impressive, and he's still that way."Juhi Yajnik jyajnik@the-scientist.comLinks within this article: Roger Kornberg http://nobelprize.org/nobel_prizes/chemistry/laureates/2006/index.P. Cramer et al., "Structural basis of transcription: RNA Polymerase II at 2.8 angstrom resolution," Science, June 8, 2001. www.the-scientist.com/pubmed/11313498A. Gnatt et al., "Structural basis of transcription: An RNA Polymerase II elongation complex at 3.3 angstrom resolution," Science, June 8, 2001. http://www.the-scientist.com/pubmed/11313499Jeremy Berg http://www.nigms.nih.gov/About/Director/Peter Fraser http://www.babraham.ac.uk/research/developmental%20genetics/fraser/index.htm"Biochemist Arthur Kornberg: A lifelong love affair with enzymes," The Scientist, September 4, 1989. http://www.the-scientist.com/article/display/9523R. Kornberg, "Chromatin Structure - repeating units of histones and DNA," Science, 1974. www.the-scientist.com/pubmed/4825889B. Maher, "The Nucleosome Untangled," The Scientist, May 1, 2006. http://www.the-scientist.com/article/display/23392Jesper Svejstrup http://science.cancerresearchuk.org/research/loc/london/lifch/svejstrupj

Kornberg wins Nobel Prize in Chemistry

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