Article abstract
Nature Structural & Molecular Biology 14, 1127 - 1133 (2007)
Published online: 11 November 2007 | doi:10.1038/nsmb1314
Mechanism of transcriptional stalling at cisplatin-damaged DNA
Gerke E Damsma1,2, Aaron Alt1, Florian Brueckner1,2, Thomas Carell1 & Patrick Cramer1,2
Abstract
The anticancer drug cisplatin forms 1,2-d(GpG) DNA intrastrand cross-links (cisplatin lesions) that stall RNA polymerase II (Pol II) and trigger transcription-coupled DNA repair. Here we present a structure-function analysis of Pol II stalling at a cisplatin lesion in the DNA template. Pol II stalling results from a translocation barrier that prevents delivery of the lesion to the active site. AMP misincorporation occurs at the barrier and also at an abasic site, suggesting that it arises from nontemplated synthesis according to an 'A-rule' known for DNA polymerases. Pol II can bypass a cisplatin lesion that is artificially placed beyond the translocation barrier, even in the presence of a G
A mismatch. Thus, the barrier prevents transcriptional mutagenesis. The stalling mechanism differs from that of Pol II stalling at a photolesion, which involves delivery of the lesion to the active site and lesion-templated misincorporation that blocks transcription.
- Center for Integrated Protein Science CIPSM, Department of Chemistry and Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
- Gene Center Munich, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
Correspondence to: Thomas Carell1 e-mail: thomas.carell@cup.uni-muenchen.de
Correspondence to: Patrick Cramer1,2 e-mail: cramer@LMB.uni-muenchen.de
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Post-phosphorylation prolyl isomerisation of gephyrin represents a mechanism to modulate glycine receptors functionThe EMBO Journal Article (04 Apr 2007)
High-efficiency bypass of DNA damage by human DNA polymerase QThe EMBO Journal Article (10 Nov 2004)
Mechanisms of accurate translesion synthesis by human DNA polymerase ηThe EMBO Journal Article (15 Jun 2000)
See all 14 matches for Research
