Redundant pathways for removal of defective RNA polymerase II complexes at a promoter-proximal pause checkpoint.

Autor: Blears D; Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Lou J; Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Fong N; RNA Bioscience Initiative, Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, PO Box 6511, Aurora, CO 80045, USA., Mitter R; Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Sheridan RM; RNA Bioscience Initiative, Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, PO Box 6511, Aurora, CO 80045, USA., He D; Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Dirac-Svejstrup AB; Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Bentley D; RNA Bioscience Initiative, Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, PO Box 6511, Aurora, CO 80045, USA., Svejstrup JQ; Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Electronic address: jsvejstrup@sund.ku.dk.
Jazyk: angličtina
Zdroj: Molecular cell [Mol Cell] 2024 Dec 19; Vol. 84 (24), pp. 4790-4807.e11. Date of Electronic Publication: 2024 Nov 05.
DOI: 10.1016/j.molcel.2024.10.012
Abstrakt: The biological purpose of Integrator and RNA polymerase II (RNAPII) promoter-proximal pausing remains uncertain. Here, we show that loss of INTS6 in human cells results in increased interaction of RNAPII with proteins that can mediate its dissociation from the DNA template, including the CRL3 ARMC5 E3 ligase, which ubiquitylates CTD serine 5 -phosphorylated RPB1 for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors acting at the promoter-proximal pause, including Integrator, DSIF, and capping enzyme. This ARMC5 checkpoint normally curtails a sizeable fraction of RNAPII transcription, and ARMC5 knockout cells produce more uncapped transcripts. When both the Integrator and CRL3 ARMC5 turnover mechanisms are compromised, cell growth ceases and RNAPII with high pausing propensity disperses from the promoter-proximal pause site into the gene body. These data support a model in which CRL3 ARMC5 functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity.
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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