POLR2G promotes transcription termination by facilitating XRN2 association with elongating RNA polymerase II

Transcription termination by RNA polymerase II (Pol II) prevents polymerase readthrough beyond annotated genes and limits transcriptional interference. Although XRN2-mediated RNA degradation is central to the torpedo model of transcription termination, how XRN2 is coupled to elongating Pol II in mammalian cells remains incompletely understood. Here, we used an endogenous AID2-POLR2G depletion system in HepG2 cells to examine the immediate role of the Pol II stalk subunit POLR2G/RPB7. Acute POLR2G depletion reduced promoter-proximal POLR2A occupancy, accompanied by lower nascent transcription across annotated transcription units. Unexpectedly, downstream of transcription end sites, increased POLR2A occupancy coincided with directional nascent transcription. Besides other Pol II subunits, POLR2G-associated proteomics recovered XRN2. Structural analysis of a published Rat1-bound Pol II termination complex, Ser2-phosphorylated Pol II (Ser2P Pol II) co-immunoprecipitation and XRN2 ChIP-qPCR collectively support a role for POLR2G in promoting XRN2 association with elongating Pol II at gene 3' ends. Re-expression of full-length POLR2G or its XRN2-associated RNA-binding domain reduced readthrough, whereas the N-terminal domain did not. Together, these findings support a model in which POLR2G contributes to efficient transcription termination by facilitating XRN2 association with elongating Pol II.