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Dangerous twosomes

How cells spot cancer causing mutations

Munich, 02/09/2007

Sunlight is the leading cause of skin cancer. When cells are exposed to its UV rays adjacent building blocks of DNA, two thymines, can form a chemical unit by connecting with each other. These bulky lesions are a major obstacle during transcription, the transfer of genetic information from DNA into mRNA, an intermediary molecule. Transcription’s most important factor, RNA polymerase II, is blocked by thymine dimers which in turn induces assembly of the repair machinery and correction of the DNA lesion. Professor Patrick Cramer and Professor Thomas Carell, both at Ludwig-Maximimilians-Universität (LMU) Munich and principle investigators within the newly established “Center of Excellence for Integrated Protein Science” now offer a detailed view of the first steps of “transcription-coupled repair (TCR)” at the atomic level. As reported in Science, this yielded some surprising results: In a first step, thymine dimers slow down transcription considerably. Then, as counterpart to the lesion the newly synthesized RNA molecule receives a specific building block called uracil. This mismatch stalls RNA polymerase II completely. “The assumption was that this is followed by considerable structural changes in the enzyme,” says Cramer. “But our results show these to be marginal. This suggests a new mechanism for coupling gene transcription and repair.”

The researchers were able to obtain crystal structures from the enzyme together with lesion-containing DNA strands and the newly synthesized RNA molecules. These revealed the thymine dimer at various positions in the polymerase. Further studies showed that the dimer in combination with the uracile prevents both DNA and RNA strands from being further transported within the enzyme – which effectively ends the transcription process. “It’s likely that the stably stalled complex of enzyme, DNA and RNA simply opens a big enough time window for assembly of the cellular repair machinery,” says Carell. Just how important a factor time can be shows another recent study. A collaboration between Professor Wolfgang Zinth, Department of Physics, LMU Munich, Professor Carell and researchers at Ohio State University revealed the temporal sequence of events that lead to the formation of thymine dimers in the first place. “Dimerization of thymines occurs only in the picosecond, that is a trillionth of a second, after absorption of UV light,” says Zinth. “This is an extremely short time span and allows only the dimerization of thymines which have already been in a favorable position for the chemical bonding. Since this is a rare occurrence in DNA the damage caused by UV light is reduced to a minimum.”

 

Contact:
Professor Dr. Thomas Carell
Department of Chemistry and Biochemistry, LMU Munich
Tel.: +49-89-2180-77750
Fax: +49-89-2180-77756
E-Mail: Thomas.Carell@cup.uni-muenchen

Professor Dr. Patrick Cramer
Managing Director of the Gene Center, LMU Munich, and at the
Department of Chemistry and Biochemistry, LMU Munich
Tel.: 089-2180-76965
Fax: 089-2180-76999
E-Mail: cramer@lmb.uni-muenchen.de

Professor Dr. Wolfgang Zinth
Department of Physics, LMU Munich
Tel.: +49-89-2180-9201
Fax: +49-89-2180-9202
E-Mail: zinth@physik.uni-muenchen.de

Publications:
Florian Brückner, Ulrich Hennecke, Thomas Carell, Patrick Cramer
CPD Damage Recognition by Transcribing RNA Polymerase II
Science, February 9, 2007

Wolfgang J. Schreier, Tobias E. Schrader, Florian O. Koller, Peter Gilch, Carlos E. Crespo-Hernández, Vijay Swaminathan, Thomas Carell, Wolfgang Zinth, Bern Kohler
Thymine Dimerization in DNA is an Ultrafast Photoreaction
Science, February 2, 2007

 

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