RT Journal
A1 Chakraborty, Alina
A1 Cadix, Mandy
A1 Relier, Sébastien
A1 Taricco, Nicolò
A1 Alaeitabar, Tina
A1 Devaux, Alexandre
A1 Labbé, Céline M.
A1 Martineau, Sylvain
A1 Heneman-Masurel, Amélie
A1 Gestraud, Pierre
A1 Inga, Alberto
A1 Servant, Nicolas
A1 Vagner, Stéphan
A1 Dutertre, Martin
T1 Compartment-specific and ELAVL1-coordinated regulation of intronic polyadenylation isoforms by doxorubicin
JF Genome Research 
JO Genome Research 
YR 2022 
FD July 01 
VO 32 
IS 7 
SP 1271 
OP 1284 
DO 10.1101/gr.276192.121 
UL http://genome.cshlp.org/content/32/7/1271.abstract 
AB Intronic polyadenylation (IPA) isoforms, which contain alternative last exons, are widely regulated in various biological processes and by many factors. However, little is known about their cytoplasmic regulation and translational status. In this study, we provide the first evidence that the genome-wide patterns of IPA isoform regulation during a biological process can be very distinct between the transcriptome and translatome, and between the nucleus and cytosol. Indeed, by 3′-seq analyses on breast cancer cells, we show that the genotoxic anticancer drug, doxorubicin, preferentially down-regulates the IPA to the last-exon (IPA:LE) isoform ratio in whole cells (as previously reported) but preferentially up-regulates it in polysomes. We further show that in nuclei, doxorubicin almost exclusively down-regulates the IPA:LE ratio, whereas in the cytosol, it preferentially up-regulates the isoform ratio, as in polysomes. Then, focusing on IPA isoforms that are up-regulated by doxorubicin in the cytosol and highly translated (up-regulated and/or abundant in polysomes), we identify several IPA isoforms that promote cell survival to doxorubicin. Mechanistically, by using an original approach of condition- and compartment-specific CLIP-seq (CCS-iCLIP) to analyze ELAVL1-RNA interactions in the nucleus and cytosol in the presence and absence of doxorubicin, as well as 3′-seq analyses upon ELAVL1 depletion, we show that the RNA-binding protein ELAVL1 mediates both nuclear down-regulation and cytosolic up-regulation of the IPA:LE isoform ratio in distinct sets of genes in response to doxorubicin. Altogether, these findings reveal differential regulation of the IPA:LE isoform ratio across subcellular compartments during drug response and its coordination by an RNA-binding protein.