Cleavage factor Im is a key regulator of 3′ UTR length

In eukaryotes, the 3' ends of RNA polymerase II-transcribed RNAs are generated in the majority of cases by site-specific endonucleolytic cleavage, followed by the addition of a poly(A) tail. Through alternative polyadenylation, a gene can give rise to multiple mRNA iso-forms that differ in the length of their 3' UTRs and hence in their susceptibility to post-transcriptional regulatory factors such as microRNAs. A series of recently conducted high-throughput studies of poly(A) site usage revealed an extensive tissue-specific control and drastic changes in the length of mRNA 3' UTRs upon induction of proliferation in resting cells. To understand the dynamics of poly(A) site choice, we recently identified binding sites of the major pre-mRNA 3' end processing factors - cleavage and polyadenylation specificity factor (CPSF), cleavage stimulation factor (CstF), and cleavage factor I-m (CF I-m)-and mapped polyadenylation sites in HEK293 cells. Our present study extends previous findings on the role of CF I-m in alternative polyadenylation and reveals that subunits of the CF I-m complex generally control 3' UTR length. More specifically, we demonstrate that the loss-of-function of CF I-m 68 and CF I-m 25 but not of CF I-m 59 leads to a transcriptome-wide increase in the use of proximal polyadenylation sites in HEK293 cells.