RPAP2 is a multifunctional regulator of RNA polymerase II (Pol II) that controls transcription through both catalytic and scaffolding mechanisms. As a Ser5-specific CTD phosphatase, RPAP2 recognizes phosphorylated Ser7 on the Pol II C-terminal domain (CTD) and mediates Ser5 dephosphorylation, promoting snRNA gene transcription 1. Beyond phosphatase activity, RPAP2 functions as a transcription checkpoint regulator by inhibiting pre-initiation complex (PIC) assembly through steric interference with TFIIF-Pol II interactions 2. RPAP2 also participates in pre-mRNA 3'-end formation of protein-coding genes via direct interaction with Pol II subunit Rpb6 3. Additionally, RPAP2 controls Pol II nuclear availability by mediating its cytoplasm-to-nucleus transport coupled with nucleocytoplasmic shuttling 4. Beyond transcription, RPAP2 functions downstream of EIF2AK3/PERK in the endoplasmic reticulum unfolded protein response, dephosphorylating ERN1 to trigger apoptosis during failed ER-stress adaptation [UniProt annotation]. Clinically, elevated RPAP2 levels correlate with poor survival in hepatocellular carcinoma, with RPAP2 stability regulated by FBXW7-mediated degradation and USP7-mediated stabilization 5. RPAP2 has also been identified as a potential therapeutic target in acute respiratory distress syndrome 6.