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Compromised Transcriptional Elongation Stimulates Initiation in Human Cells [4sU-DRB-seq]

ABSTRACT: P-TEFb is a well-established positive regulator of pause release of Pol II. The human PAF1 complex (PAF1C), consisting of PAF1, CTR9, CDC73, CTR9 and SKI8, plays critical roles in transcription and RNA processing, yet whether and how it regulates pause release is under debate. To address these issues, we further analyzed effects of PAF1 loss on pause release while using P-TEFb inhibition as a positive control. We found that besides increasing pause of Pol II, P-TEFb inhibition decreases and increases chromatin occupancy of PAF1C and Integrator, respectively. In contrast, acute PAF1 degradation increases the occupancy of Integrator and ARMC5, suggesting a positive role of the PAF1C in pause release by preventing promoter-proximal termination and Pol II degradation. Moreover, combined P-TEFb inhibition and PAF1 degradation increase pause of Pol II more than either treatment alone does, suggesting a cooperativity between them in pause release. Importantly, either P-TEFb inhibition or PAF1 degradation increases occupancy of initiation factors, suggesting that elongation perturbation may stimulate initiation, contrary to conclusions of three previous studies. Altogether, our results firmly established the PAF1C as a critical positive regulator of pause release and advanced current understanding of the connection between pause and initiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295212 | GEO | 2026/04/06

REPOSITORIES: GEO

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