Effect of splicing factor mutations on biological processes beyond RNA splicing. (A) The positive transcription elongation factor complex, P-TEFb, composed of cyclin-dependent kinase 9 (CDK9) and cyclin T1, stimulates synthesis of RNA through phosphorylation of RNA polymerase II (Pol II). However, when bound to 7SK snRNA, HEXIM,1 LARP7, and MePCE (7SK snRNA methyl phosphate capping enzyme), P-TEFb is catalytically inactive and represses transcription by suppressing the release of paused polymerase II. The transition of P-TEFb from repressive to active complexes depends on multiple factors including SRSF2. Mutant SRSF2, however, loses its ability to extract P-TEFb from the 7SK complex due to increased RNA binding. This results in elevated R-loops (nascent RNA-DNA hybrids formed during transcription leaving the nontemplate DNA strand looping out) and subsequent replication stress and activation of the ataxia telangiectasia and Rad3-related protein (ATR)-Chk1 pathway. (B) Mutations at proline 95 residue in SRSF2 change its RNA-binding affinity from G-rich (GGWG) to C-rich (C/GCWG) motifs (W = A/U) inducing transcriptome-wide missplicing events. Several mRNA isoforms promoted by SRSF2 mutants harbor a PTC and are therefore potential targets of NMD. Moreover, SRSF2 mutants further enhance NMD by promoting recruitment of EJC factors (eIF4A3, MAGOH, and Y14) to mRNAs downstream of PTCs within the nucleus. This subsequently enhances the association of several NMD factors (UPF3B, UPF2, and UPF1) to mRNA within the cytoplasm, thereby enhancing mRNA decay.