Loss of CFIm activates YAP/TAZ and connects mRNA cleavage and polyadenylation inhibition to BRCAness.

The YAP/TAZ transcription program plays a crucial role in development, regeneration, and cancer. CFIm is a master regulator of mRNA alternative polyadenylation (APA). Loss of CFIm function was shown in human cancer but its impact on the gene expression program is not well characterized. Here we report the discovery that loss of CFIm in cancer cells activates YAP/TAZ and promotes therapeutic resistance. We identified a CFIm-NEDD4L-LATS1 regulatory axis that suppressed YAP/TAZ activation. Furthermore, we found that CFIm loss in the presence of mRNA cleavage and polyadenylation (CPA) inhibition repressed key DNA repair genes in the Fanconi anemia (FA) and homology-directed repair (HDR) pathways, which induced the BRCAness phenotype and aggravated DNA damage. Our study reveals a hidden link between mRNA 3' end processing and the YAP/TAZ transcription program in addition to illustrating how CFIm function impacts the selection of therapeutic agents in cancer.