Structural basis of Integrator-dependent RNA polymerase II termination

Area of Science:

• Molecular Biology
• Structural Biology
• Gene Regulation

Background:

• The Integrator complex is known to bind paused elongation complexes and cleave nascent RNA during transcription termination.
• The mechanism by which Integrator removes RNA polymerase II (Pol II) from the DNA template after transcription has remained unclear.

Purpose of the Study:

• To elucidate the structural mechanisms underlying RNA polymerase II transcription termination by the Integrator complex.
• To understand the role of different Integrator subunits and associated factors in the termination process.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structures of the Integrator-PP2A complex in multiple functional states.
• Analysis of pre-termination, post-termination, and inactive complex structures.

Main Results:

• A novel INTS10-INTS13-INTS14-INTS15 module was identified in the pre-termination complex, potentially involved in opening the DSIF DNA clamp.
• The INTS3 subunit and SOSS factors were shown to prevent Pol II re-binding in the post-termination complex.
• The INTS6 subunit was found to block the PP2A phosphatase active site in the inactive complex.

Conclusions:

• A three-step model for Integrator-mediated Pol II transcription termination is proposed, involving significant structural rearrangements.
• These findings provide atomic-level insights into the regulation of transcription termination by the Integrator complex.