Martin DUTERTRE

Team « RNA Biology, Signaling and Cancer »

INSERM U1278, UMR 3348 CNRS

Institut Curie, Orsay, France

Regulation of intronic polyadenylation (IPA) by genotoxic anticancer drugs

reveals microprotein-coding IPA isoforms

Intronic polyadenylation (IPA) is a recently described mechanism that produces transcript isoforms with alternative last exons in thousands of human genes. We found that IPA isoforms are widely regulated in cancer cell response to genotoxic anticancer drugs (i.e., the ratio of IPA to last-exon isoforms is most often decreased by doxorubicin and increased by cisplatin) and impact cancer cell survival to these drugs. We also found that most IPA isoforms are associated with polysomes, suggesting that they are translated. Finally, we identified short IPA isoforms that are generated in the annotated 5'-untranslated region of protein-coding genes (5’UTR-IPA isoforms) but are functional and encode microproteins (an emerging class of small proteins). We are now characterizing this new class of genes that generate both an upstream short mRNA (usmRNA) encoding a microprotein and a full-length mRNA isoform encoding a canonical protein.