1. XPF-dependent DNA breaks and RNA polymerase II arrest induced by antitumor DNA interstrand crosslinking-mimetic alkaloids
- Author
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Federico Gago, Sascha Feuerhahn, Carlos M. Galmarini, Jean-Marc Egly, Marta Martínez-Diez, Juan A. Bueren-Calabuig, and Christophe Giraudon
- Subjects
Models, Molecular ,Transcriptional Activation ,Base pair ,DNA polymerase ,Sp1 Transcription Factor ,DNA polymerase II ,Clinical Biochemistry ,Antineoplastic Agents ,Dioxoles ,Biochemistry ,Tetrahydroisoquinolines ,DNA Interstrand Crosslinking ,Drug Discovery ,Deoxyribonuclease I ,Humans ,Molecular Biology ,Antineoplastic Agents, Alkylating ,Polymerase ,Transcription bubble ,Pharmacology ,DNA clamp ,biology ,DNA Breaks ,General Medicine ,DNA ,Endonucleases ,Molecular biology ,DNA-Binding Proteins ,Cross-Linking Reagents ,biology.protein ,Molecular Medicine ,Primase ,RNA Polymerase II ,Trabectedin - Abstract
SummaryTrabectedin and Zalypsis are two potent anticancer tetrahydroisoquinoline alkaloids that can form a covalent bond with the amino group of a guanine in selected triplets of DNA duplexes and eventually give rise to double-strand breaks. Using well-defined in vitro and in vivo assays, we show that the resulting DNA adducts stimulate, in a concentration-dependent manner, cleavage by the XPF/ERCC1 nuclease on the strand opposite to that bonded by the drug. They also inhibit RNA synthesis by: (1) preventing binding of transcription factors like Sp1 to DNA, and (2) arresting elongating RNA polymerase II at the same nucleotide position regardless of the strand they are located on. Structural models provide a rationale for these findings and highlight the similarity between this type of DNA modification and an interstrand crosslink.
- Published
- 2011