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ReportsCPD Damage Recognition by Transcribing RNA Polymerase IICells 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. * 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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