Assembly mechanism of Integrator’s RNA cleavage module
Copyright policy )Assembly mechanism of Integrator’s RNA cleavage module
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 (IP6). Our data explain several neurodevelopmental disorders caused by BRAT1, WDR73, and INTS11 mutations as Integrator assembly defects and reveal that IP6 is an essential co-factor for cleavage module maturation.
Molecular Cell, 84 (15)
ISSN:1097-2765
ISSN:1097-4164
- ETH Zurich Switzerland
- Institute of Molecular Biology and Biophysics Switzerland
RNA Cleavage, Cell Nucleus, WDR73, lethal neonatal rigidity and multifocal seizure syndrome, Phytic Acid, transcription attenuation, RNA Nucleotidyltransferases, NEDCAS, HEK293 Cells, BRAT1, Galloway-Mowat Syndrome, Catalytic Domain, non-coding RNA processing; RNA polymerase II transcription; transcription attenuation; inositol hexaphosphate; BRAT1; WDR73; lethal neonatal rigidity and multifocal seizure syndrome; NEDCAS; Galloway-Mowat Syndrome, Mutation, inositol hexaphosphate, Humans, RNA polymerase II transcription, non-coding RNA processing, Protein Binding
RNA Cleavage, Cell Nucleus, WDR73, lethal neonatal rigidity and multifocal seizure syndrome, Phytic Acid, transcription attenuation, RNA Nucleotidyltransferases, NEDCAS, HEK293 Cells, BRAT1, Galloway-Mowat Syndrome, Catalytic Domain, non-coding RNA processing; RNA polymerase II transcription; transcription attenuation; inositol hexaphosphate; BRAT1; WDR73; lethal neonatal rigidity and multifocal seizure syndrome; NEDCAS; Galloway-Mowat Syndrome, Mutation, inositol hexaphosphate, Humans, RNA polymerase II transcription, non-coding RNA processing, Protein Binding
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