A Complex of U1 snRNP with Cleavage and Polyadenylation Factors Controls Telescripting, Regulating mRNA Transcription in Human Cells

Full-length transcription in the majority of human genes depends on U1 snRNP (U1) to co-transcriptionally suppress transcription-terminating premature 3′ end cleavage and polyadenylation (PCPA) from cryptic polyadenylation signals (PASs) in introns. However, the mechanism of this U1 activity, termed telescripting, is unknown. Here, we captured a complex, comprising U1 and CPA factors (U1-CPAFs), that binds intronic PASs and suppresses PCPA. U1-CPAFs are distinct from U1-spliceosomal complexes; they include CPA’s three main subunits, CFIm, CPSF, and CstF; lack essential splicing factors; and associate with transcription elongation and mRNA export complexes. Telescripting requires U1:pre-mRNA base-pairing, which can be disrupted by U1 antisense oligonucleotide (U1 AMO), triggering PCPA. U1 AMO remodels U1-CPAFs, revealing changes, including recruitment of CPA-stimulating factors, that explain U1-CPAFs’ switch from repressive to activated states. Our findings outline this U1 telescripting mechanism and demonstrate U1’s unique role as central regulator of pre-mRNA processing and transcription. [Display omitted] •U1 snRNP (U1) is in a complex with cleavage and polyadenylation factors (U1-CPAFs)•U1-CPAFs bind and suppress PASs as U1 snRNA 5′ is base paired with pre-mRNA nearby•U1 base-pairing inhibition remodels U1-CPAFs and recruits CPA-stimulating factors•U1-CPAFs interact with mRNA processing, transport, and transcription factors So et al. show that a complex of U1 snRNP (U1) with cleavage and polyadenylation factors (CPAFs) binds pre-mRNAs’ cryptic polyadenylation signals, suppressing premature transcription termination and linking multiple mRNA processing and transcription factors. U1 PAS suppression, called telescripting, is required for full-length transcription and regulates 3′ UTR length.