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The beginnings of molecular evolution

Munich, 11/15/2007

According to the so-called “RNA world hypothesis” the nucleic acid RNA dominated the living world early in evolution and before DNA existed. RNA acted as the long-term store of genetic information and as the catalyst of all processes to support cellular or pre-cellular life. There is no definite proof of an early RNA world, but evidence is accumulating. Professor Patrick Cramer, director of the Gene Center at the Ludwig-Maximilians-Universität (LMU) München, and two of his co-workers, Elisabeth Lehmann and Florian Bruckner, now provide a missing link in molecular evolution – especially in regards to the RNA world hypothesis. As reported in the science journal Nature an essential enzyme of recent organisms – humans among them – possesses an ability that reaches back to the RNA world. “This enzyme is called RNA polymerase II,” says Cramer. “Its special ability makes its core one of the oldest or even the oldest protein.”

Transcription is crucial for the survival and functioning of cells: In this process genetic information is turned into a messenger molecule, which in turn serves as a template to synthesize proteins. The template for transcription is the nucleic acid DNA which stores genetic information in all organisms. The catalyst of transcription is the enzyme RNA polymerase II, or Pol II. The messenger molecule is called mRNA. RNA is another nucleic acid and closely related to DNA. Cramer’s team was able to show that Pol II can use as a template not only DNA, but RNA as well. This surprising ability of the polymerase might date back to an RNA world where no DNA existed. “An ancestor of Pol II probably duplicated RNA genomes and only later accepted DNA as a template,” says Cramer. “This finding bridges one of the biggest gaps in our understanding of molecular evolution.”

Walter Gilbert, who was awarded the Nobel Prize in Chemistry, coined the expression “RNA world”. There are many “scientific” fathers to this hypothesis, though. Leslie Orgel, a biochemist who died earlier this month, was one of them. One point in favour of an ancient RNA world is the molecule’s versatility: RNA can act as a long-term store of genetic information and also as a chemical catalyst, that is, an enzyme. This last ability is necessary to multiply itself or other stores of genetic information. In Cramer’s experiments Pol II was able to use RNA as a template and in this process prolong another RNA molecule – without any DNA present. “This ancient reaction is still used in today’s world,” says Cramer. “The RNA genome of the Hepatitis Delta Virus is being duplicated this way. There are apparently more virus-like pathogens which use the ability of Pol II to synthesize an RNA molecule that is complementary to an RNA template.”

A crystallographic analysis revealed that the RNA template and the newly synthesized RNA strand occupy the same active site in the enzyme as the DNA template and its messenger RNA during normal transcription. But RNA synthesis using an RNA template works more slowly and less effectively. “Our results suggest that Pol II developed from one of the first proteins, an early RNA replicase,” says Cramer. “This enzyme first duplicated RNA genomes and later accepted DNA templates as well. The unexpected use of RNA templates by Pol II can explain the switch from RNA genomes to DNA genomes billions of years ago.”

“Molecular basis of RNA-dependent RNA polymerase II activity”,
Elisabeth Lehmann, Florian Brückner, Patrick Cramer,
Nature, November 15, 2007

Professor Dr. Patrick Cramer
Managing Director of the Gene Center, LMU Munich,
and at the Department of Chemistry and Biochemistry, LMU Munich
Tel.: +49-89-2180-76965
Fax: +49-89-2180-76999