Assembly mechanism of Integrator's RNA cleavage module.

Autor: Sabath K; Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland., Qiu C; Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland., Jonas S; Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland. Electronic address: stefanie.jonas@mol.biol.ethz.ch.
Jazyk: angličtina
Zdroj: Molecular cell [Mol Cell] 2024 Aug 08; Vol. 84 (15), pp. 2882-2899.e10. Date of Electronic Publication: 2024 Jul 19.
DOI: 10.1016/j.molcel.2024.06.032
Abstrakt: 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 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.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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