Modulating the cleavage and polyadenylation site: from research tools to therapeutic opportunities

Abstract

Almost all protein-coding and long noncoding genes that are transcribed by RNA polymerase II employ cleavage and polyadenylation (CPA) for 3' end maturation of their nascent RNAs. More than 70% of human mRNA genes display alternative polyadenylation (APA), resulting in expression of isoforms using different polyA sites (PAS). APA isoforms often have distinct mRNA metabolism and/or contain variable coding sequences. PAS mutations and genetic variations have been implicated in a growing number of human pathological conditions, underscoring the importance of PAS usage or selection for proper gene expression. Here we review approaches that modulate the usage of specific PAS using antisense- and CRISPR-based methods. We discuss applications of these strategies in the context of human diseases. We provide our perspectives on current challenges and future directions to advance PAS modulation in APA studies and development of related therapeutics.