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-Structure paper
Title | Assembly mechanism of Integrator's RNA cleavage module. |
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Journal, issue, pages | Mol Cell, Vol. 84, Issue 15, Page 2882-2899.e10, Year 2024 |
Publish date | Aug 8, 2024 |
![]() | Kevin Sabath / Chunhong Qiu / Stefanie Jonas / ![]() |
PubMed Abstract | The modular Integrator complex is a transcription regulator that is essential for embryonic development. It attenuates coding gene expression via premature transcription termination and performs 3'- ...The modular Integrator complex is a transcription regulator that is essential for embryonic development. It attenuates coding gene expression via premature transcription termination and performs 3'-processing of non-coding RNAs. For both activities, Integrator requires endonuclease activity that is harbored by an RNA cleavage module consisting of INTS4-9-11. How correct assembly of Integrator modules is achieved remains unknown. Here, we show that BRAT1 and WDR73 are critical biogenesis factors for the human cleavage module. They maintain INTS9-11 inactive during maturation by physically blocking the endonuclease active site and prevent premature INTS4 association. Furthermore, BRAT1 facilitates import of INTS9-11 into the nucleus, where it is joined by INTS4. Final BRAT1 release requires locking of the mature cleavage module conformation by inositol hexaphosphate (IP). Our data explain several neurodevelopmental disorders caused by BRAT1, WDR73, and INTS11 mutations as Integrator assembly defects and reveal that IP is an essential co-factor for cleavage module maturation. |
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Methods | EM (single particle) |
Resolution | 3.2 - 3.9 Å |
Structure data | EMDB-18833, PDB-8r22: EMDB-18834, PDB-8r23: EMDB-18839, PDB-8r2d: |
Chemicals | ![]() ChemComp-ZN: |
Source |
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![]() | TRANSCRIPTION / Chaperone / nuclear import / Integrator complex |