Coordinated regulation of RNA polymerase II pausing and elongation progression by PAF1
Zhenning Wang, Aixia Song, Hao Xu, Shibin Hu, Bolin Tao, Linna Peng, Jingwen Wang, Jiabei Li, Jiali Yu, Li Wang, Ze Li, Xizi Chen, Mengyun Wang, Yayun Chi, Jiong Wu, Yanhui Xu, Hai Zheng, Fei Chen
Abstract
Pleiotropic transcription regulator RNA polymerase II (Pol II)-associated factor 1 (PAF1) governs multiple transcriptional steps and the deposition of several epigenetic marks. However, it remains unclear how ultimate transcriptional outcome is determined by PAF1 and whether it relates to PAF1-controlled epigenetic marks. We use rapid degradation systems and reveal direct PAF1 functions in governing pausing partially by recruiting Integrator-PP2A (INTAC), in addition to ensuring elongation. Following acute PAF1 degradation, most destabilized polymerase undergoes effective release, which presumably relies on skewed balance between INTAC and P-TEFb, resulting in hyperphosphorylated substrates including SPT5. Impaired Pol II progression during elongation, along with altered pause release frequency, determines the final transcriptional outputs. Moreover, PAF1 degradation causes a cumulative decline in histone modifications. These epigenetic alterations in chromatin likely further influence the production of transcripts from PAF1 target genes.