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TitleAssembly mechanism of Integrator's RNA cleavage module.
Journal, issue, pagesMol Cell, Vol. 84, Issue 15, Page 2882-2899.e10, Year 2024
Publish dateAug 8, 2024
AuthorsKevin Sabath / Chunhong Qiu / Stefanie Jonas /
PubMed AbstractThe 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.
External linksMol Cell / PubMed:39032489
MethodsEM (single particle)
Resolution3.2 - 3.9 Å
Structure data

18833

8r22

EMDB-18833, PDB-8r22:
INTS9-INTS11-BRAT1-WDR73 complex
Method: EM (single particle) / Resolution: 3.9 Å

18834

8r23

EMDB-18834, PDB-8r23:
INTS9-INTS11-BRAT1 complex
Method: EM (single particle) / Resolution: 3.2 Å

18839

8r2d

EMDB-18839, PDB-8r2d:
Integrator cleavage module assembly intermediate
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSCRIPTION / Chaperone / nuclear import / Integrator complex

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