Nuclear export restricts Gdown1 to a mitotic function

Christopher B Ball; Mrutyunjaya Parida; Juan F Santana; Benjamin M Spector; Gustavo A Suarez; David H Price

doi:10.1093/nar/gkac015

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Nuclear export restricts Gdown1 to a mitotic function

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Nuclear export restricts Gdown1 to a mitotic function

Christopher B Ball, Mrutyunjaya Parida, Juan F Santana, Benjamin M Spector, Gustavo A Suarez and David H Price

Nucleic acids research, Vol.50(4), pp.1908-1926

02/28/2022

DOI: 10.1093/nar/gkac015

PMCID: PMC8887472

PMID: 35048979

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Abstract

Abstract Approximately half of purified mammalian RNA polymerase II (Pol II) is associated with a tightly interacting sub-stoichiometric subunit, Gdown1. Previous studies have established that Gdown1 inhibits transcription initiation through competitive interactions with general transcription factors and blocks the Pol II termination activity of transcription termination factor 2 (TTF2). However, the biological functions of Gdown1 remain poorly understood. Here, we utilized genetic, microscopic, and multi-omics approaches to functionally characterize Gdown1 in three human cell lines. Acute depletion of Gdown1 caused minimal direct effects on transcription. We show that Gdown1 resides predominantly in the cytoplasm of interphase cells, shuttles between the cytoplasm and nucleus, and is regulated by nuclear export. Gdown1 enters the nucleus at the onset of mitosis. Consistently, genetic ablation of Gdown1 is associated with partial de-repression of mitotic transcription, and Gdown1 KO cells present with evidence of aberrant mitoses coupled to p53 pathway activation. Evidence is presented demonstrating that Gdown1 modulates the combined functions of purified productive elongation factors PAF1C, RTF1, SPT6, DSIF and P-TEFb in vitro. Collectively, our findings support a model wherein the Pol II-regulatory function of Gdown1 occurs during mitosis and is required for genome integrity.

Details

Title: Subtitle: Nuclear export restricts Gdown1 to a mitotic function
Creators: Christopher B Ball - University of Iowa
Mrutyunjaya Parida - University of Iowa
Juan F Santana - University of Iowa
Benjamin M Spector - University of Iowa
Gustavo A Suarez - Department of Biochemistry and Molecular Biology, The University of Iowa, Iowa City, IA 52242, USA
David H Price - Department of Biochemistry and Molecular Biology, The University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Nucleic acids research, Vol.50(4), pp.1908-1926
DOI: 10.1093/nar/gkac015
PMID: 35048979
PMCID: PMC8887472
NLM abbreviation: Nucleic Acids Res
ISSN: 0305-1048
eISSN: 1362-4962
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: R35 GM126908
Language: English
Date published: 02/28/2022
Academic Unit: Pathology; Biology; Biochemistry and Molecular Biology
Record Identifier: 9984288731102771

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