Molecular Basis for Impacts of DSIF on the Dynamics of RNA Polymerase II Elongation Complex

Transcription elongation is a highly regulated process involving elongation factors associated with RNA polymerase II (Pol II). DRB sensitivity-inducing factor (DSIF) is an elongation factor known to have roles in promoter-proximal pausing, elongation processivity, and nucleosomal access during transcription elongation. Although multiple studies resolved the structures of elongation complexes with DSIF and provided important insights into the roles of DSIF in transcription elongation, little is known about the impacts of DSIF on the dynamics of the elongation complex at the molecular level. Here, we used molecular dynamics simulations to elucidate the effects of DSIF on the dynamics and structure of Pol II and upstream nucleic acids, thereby gaining a mechanistic understanding of its role in transcription elongation. We determined three major sites of impact by DSIF, including the upstream nucleic acids, Pol II clamp, and active site, which potentially contribute to its role in transcription processivity. Our results showed that DSIF helps stabilize upstream DNA and RNA at the exit sites, preventing the unwinding of DNA and the folding of RNA. In addition, our results suggest that DSIF regulates the motion of the Pol II clamp to potentially maintain a proper size at the central cleft. We also observed a more dynamic active site and increased interactions between active site domains. Based on correlated motion analysis, we proposed that the impacts of DSIF on the active site have an allosteric nature that takes place through the collective motions of the Pol II clamp and nucleic acids.