8r22
INTS9-INTS11-BRAT1-WDR73 complex
Structural highlights
DiseaseBRAT1_HUMAN The disease is caused by mutations affecting the gene represented in this entry. FunctionBRAT1_HUMAN Required for activation of ATM following ionizing radiation. May act by regulating dephosphorylation of ATM.[1] Publication Abstract from PubMedThe 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(6)). Our data explain several neurodevelopmental disorders caused by BRAT1, WDR73, and INTS11 mutations as Integrator assembly defects and reveal that IP(6) is an essential co-factor for cleavage module maturation. Assembly mechanism of Integrator's RNA cleavage module.,Sabath K, Qiu C, Jonas S Mol Cell. 2024 Jul 16:S1097-2765(24)00539-2. doi: 10.1016/j.molcel.2024.06.032. PMID:39032489[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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