XPF-Dependent DNA Breaks and RNA Polymerase II Arrest Induced by Antitumor DNA Interstrand Crosslinking-Mimetic Alkaloids

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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (274 K)Download as PowerPoint slideHighlights► The adduct-containing DNA is hydrolyzed by the XPF/ERCC1 endonuclease ► Trabectedin and Zalypsis prevent binding of the transcription factor Sp1 to DNA ► Both DNA-drug adducts arrest RNA polymerase II transcription elongation ► The structural differences between the two drugs are translated into macroscopic oobservables