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10/11/06

RNA 101: A primer on Roger Kornberg's work

By MITZI BAKER

The Nobel Prize in Chemistry went to Roger Kornberg, PhD, for his work in understanding how DNA is converted into RNA, a process known as transcription. Here’s an introduction to transcription and the contribution that earned Kornberg the award.

Q: What is RNA and how does it relate to DNA?

A: Every cell in an organism has the same DNA. For cells to have different functions—such as heart cells, liver cells and neurons—they use their genetic blueprints differently, like someone having access to an encyclopedia and only reading the articles pertaining to history. For information to be transmitted selectively depends on the permanent encyclopedia of DNA making a transcribed note of RNA that then gets translated into a particular protein.

Q: What is transcription?

A: The process of making RNA’s fleeting protein-coding instructions from DNA is known as transcription. Instead of directly using the DNA genetic blueprint, the cell makes copies of it in the nucleus, in the form of RNA. The RNA then carries the instructions out of the nucleus, into the rest of the cell to make proteins.

Q: What did Kornberg discover about transcription?

A: RNA polymerase is the enzyme that makes RNA from DNA through transcription. For more than 30 years Kornberg’s lab has been studying RNA and RNA polymerase, determining the complex arrangement of the 30,000 atoms in the RNA polymerase. They have identified how the machinery works, dubbing parts of the complex “jaws,” “clamp” and “funnel,” based on their function in trapping DNA and locking on to it. Later studies elucidated the inner and middle layers of the protein complex, observing a DNA “docking site” and a protein “finger” that pokes into the active part of the enzyme, possibly to slow down the transcription process so that the strands of DNA and newly made RNA can separate properly. They also created an image of the polymerase in action, something that hadn’t been done before.

Q: How does Roger Kornberg’s Nobel-Prize-winning work relate to the studies for which Andrew Fire won the 2006 Nobel Prize in Physiology or Medicine?

A: The central dogma of genetics holds that double-stranded DNA makes single-stranded messenger RNA (or mRNA) that makes protein, which is the workhorse of the cell. Kornberg elucidated the mechanism for making mRNA. Fire and his collaborator Craig Mello from from the University of Massachusetts Medical School showed that an unusual entity—double-stranded RNA—can destroy an mRNA with a matching sequence of nucleic acids. By eliminating the mRNA, double-stranded RNA halts the orderly progression of DNA to mRNA to protein. The process is now known as RNAi, or RNA interference. Like transcription, RNAi appears to work in all plants, animals and even lower organisms.

Q: When did Kornberg do this work?

A: Kornberg’s first publication, in 1965, was about RNA polymerase, but he didn’t devote his attention to the enzyme in earnest until the mid-’70s. Kornberg’s group published groundbreaking findings in 2000, constructing a model of how 12 individual subunits of the enzyme fit together to form the entire RNA polymerase complex. In 2001 they outlined the structure of the innermost layer. And in 2004, they published two papers detailing the middle layer, including a snapshot of the enzyme in action. All of his major milestones in the progressive elucidation of RNA polymerase structure were published in the journal Science. The Kornberg lab continues to explore the inner workings of RNA polymerase in increasing depth.

Q: Why should people care about these RNA discoveries?

A: Both of these discoveries were rooted in basic research, and they both prove how basic research can eventually prove useful. Without RNA polymerase, all the DNA contained in the human genome would be useless. Understanding how RNA polymerase directs transcription helps explain how the process sometimes goes awry, leading to birth defects, cancer and other diseases. Similarly, the RNAi process is a fundamental biological mechanism. The discovery of RNAi has opened up possible gene therapy for diseases caused by an overabundance of normal protein. RNAi could additionally be harnessed to block viral infections and to stop the overproduction of the protein that drives macular degeneration, the leading cause of blindness.

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