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Science 9 February 2007:
Vol. 315. no. 5813, pp. 859 - 862
DOI: 10.1126/science.1135400
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Reports

CPD Damage Recognition by Transcribing RNA Polymerase II

Florian Brueckner,1,2,3 Ulrich Hennecke,1,2 Thomas Carell,1,2* Patrick Cramer1,2,3*

Cells use transcription-coupled repair (TCR) to efficiently eliminate DNA lesions such as ultraviolet light–induced cyclobutane pyrimidine dimers (CPDs). Here we present the structure-based mechanism for the first step in eukaryotic TCR, CPD-induced stalling of RNA polymerase (Pol) II. A CPD in the transcribed strand slowly passes a translocation barrier and enters the polymerase active site. The CPD 5'-thymine then directs uridine misincorporation into messenger RNA, which blocks translocation. Artificial replacement of the uridine by adenosine enables CPD bypass; thus, Pol II stalling requires CPD-directed misincorporation. In the stalled complex, the lesion is inaccessible, and the polymerase conformation is unchanged. This is consistent with nonallosteric recruitment of repair factors and excision of a lesion-containing DNA fragment in the presence of Pol II.

1 Munich Center for Integrated Protein Science CiPSM, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
2 Department of Chemistry and Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
3 Gene Center Munich, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.

* To whom correspondence should be addressed. E-mail: thomas.carell{at}cup.uni-muenchen.de (T.C.); cramer{at}lmb.uni-muenchen.de (P.C.)

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