Research SummaryThe specificity and the mechanism of Star-PAP mediated alternative polyadenylation and 3'-end processing in gene regulation
All eukaryotic mRNAs (except those encoding histones) harbour poly(A) tail at the 3’-end that is required for the stability and efficient translation of the mRNA. There are two major poly (A) polymerases (PAPs) in the nucleus involved in general mRNA polyadenylation - canonical PAPα and Star-PAP. Interestingly, more than 70% of genes in humans are alternatively polyadenylated (APA) at the 3'-UTR, thus encoding multiple mRNA isoforms with different UTR lengths. The differential stability of mRNAs mediated by 3'-UTR isoforms modulate gene expression in human diseases such as cardiovascular disease (CVD) and cancer.
We are interested in understanding the mechanism and regulation of alternative polyadenylation by PAPs, and its effect on human diseases. We mainly focus on the non-canonical PAP, Star-PAP which selectively polyadenylates genes involved in oxidative stress response, apoptosis and cardiac hypertrophy. We hypothesize that specific UTR elements selects distinct PAP that determines mRNA target specificity. We have defined role of Star-PAP in APA of select mRNAs and identified the sepcificity elements that excludes PAPα from Star-PAP target UTRs. Our results demonstrate a novel role of phopshorylation where distinct phopshorylation site(s) on Star-PAP determines mRNA targets to be polyadenylated that mediates signal regulated target gene specificty. A model depicting PAP selection at the 3'-end is shown below.
Figure Legend: 3’-end PAP selection: model depicts a PAP switch/selection at the 3’end of a gene favouring a particular PAP is determined by the cis-elements present on the target UTR RNA