Bifurcated intronic polyadenylation profile in the pan-cancer transcriptome renders multifaceted functions of C-terminome

Background: Alternative cleavage and polyadenylation (APA) occurring in introns can lead to premature transcriptional termination and generate shorter mRNA isoforms from genes. While intronic APA has been suggested to produce shorter protein isoforms in the proteome, its physiological relevance remains unclear.Results: Through APA-targeted profiling, we discovered that intronic APA events in the transcriptome exhibit a bifurcated pattern. Upon changes in cellular mammalian target of rapamycin activity, a group of genes increases intronic APA while others decrease intronic APA. This discrete pattern of intronic APA persists in normal tissues and tumor samples across 10 cancer types examined in The Cancer Genome Atlas transcriptome datasets. In silico interrogations on the conserved intronic APA event-associated rearrangement of protein functional domains in the Pfam database led to unexpected findings. The bifurcated intronic APA profile indicates a disease condition-specific activation and deactivation of Pfam domain among the same protein family, highlighting the potential pathogenicity of intronic APA. Intronic APA also features a disease condition-associated regulation of protein length, resulting in a multifaceted C-terminome in cancer that could be pathogenic. Moreover, studies on JMJD6 intronic APA isoform-specific functions suggest that a multifaceted pathogenic C-terminone exists in the cancer proteome.Conclusions: Unlike the prevalent shortening of transcripts by 3'-untranslated region APA in the cancer transcriptome, we demonstrate that intronic APA is a discrete molecular signature in both normal tissue and cancer transcriptomes. We suggest that the dynamics of intronic APA contribute to the multifunctionality of the C-terminome in the cancer proteome.