Lurbinectedin specifically triggers the degradation of phosphorylated RNA Polymerase II and the formation of DNA breaks in cancer cells

We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent anti-tumorigenic activity across several cancer cell lines and tumor xenografts. This drug currently undergoing clinical evaluation in ovarian, breast and small-cell lung cancer patients inhibits the transcription process through (1) its binding to CG rich sequences, mainly located around the promoter of protein coding genes; (2) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery and (3) the generation of DNA breaks. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism.