title: XPF-dependent DNA breaks and RNA polymerase II arrest induced by antitumor DNA interstrand crosslinking-mimetic alkaloids.
abstract: Trabectedin 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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UdS, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France.
authors.forename: Sascha
authors.initials: S
authors.lastname: Feuerhahn
authors.forename: Christophe
authors.initials: C
authors.lastname: Giraudon
authors.forename: Marta
authors.initials: M
authors.lastname: Martínez-Díez
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bueren-Calabuig
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D053960:DNA Breaks / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology*; D004720:Endonucleases / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D004149:Dioxoles; C500383:PM 00104; D016329:Sp1 Transcription Factor; D044005:Tetrahydroisoquinolines; C095888:xeroderma pigmentosum group F protein; D004247:DNA; D012319:RNA Polymerase II; C071447:ERCC1 protein, human; D004720:Endonucleases; D003850:Deoxyribonuclease I; D000077606:Trabectedin