SCAF4 and SCAF8, mRNA Anti-Terminator Proteins

Accurate regulation of mRNA termination is required for correct gene expression. Here, we describe a role for SCAF4 and SCAF8 as anti-terminators, suppressing the use of early, alternative polyadenylation (polyA) sites. The SCAF4/8 proteins bind the hyper-phosphorylated RNAPII C-terminal repeat domain (CTD) phosphorylated on both Ser2 and Ser5 and are detected at early, alternative polyA sites. Concomitant knockout of human SCAF4 and SCAF8 results in altered polyA selection and subsequent early termination, leading to expression of truncated mRNAs and proteins lacking functional domains and is cell lethal. While SCAF4 and SCAF8 work redundantly to suppress early mRNA termination, they also have independent, non-essential functions. SCAF8 is an RNAPII elongation factor, whereas SCAF4 is required for correct termination at canonical, distal transcription termination sites in the presence of SCAF8. Together, SCAF4 and SCAF8 coordinate the transition between elongation and termination, ensuring correct polyA site selection and RNAPII transcriptional termination in human cells. [Display omitted] •Human SCAF4 and SCAF8 couple RNAPII Ser2P- and Ser5P-binding and RNA processing•SCAF4 and SCAF8 bind nascent RNA upstream of early polyadenylation sites•SCAF4 and SCAF8 prevent early mRNA transcript cleavage and polyadenylation•Lack of SCAF4 and SCAF8 result in truncated protein products and is cell lethal Eukaryotic anti-terminator proteins suppress usage of early polyadenylation sites to prevent production of truncated proteins.