Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability
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- Morteza Chalabi Hajkarim
- Department of Medicine Haematology & Oncology, Columbia University, New York City, NY 10032, USA
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- Nafiseh Chalabi Hagkarim
- Institute for Cancer and Genomic Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UK
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- Toru Suzuki
- Division of RNA and Gene Regulation, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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- Toshinobu Fujiwara
- Laboratory of Biochemistry, Kindai University, Higashi-Osaka City 577-8502, Japan
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- G. Sebastiaan Winkler
- School of Pharmacy, University of Nottingham, Nottingham NG7 3RD, UK
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- Grant S. Stewart
- Institute for Cancer and Genomic Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UK
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- Roger J. Grand
- Institute for Cancer and Genomic Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UK
書誌事項
- 公開日
- 2023-07-17
- 資源種別
- journal article
- 権利情報
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- https://creativecommons.org/licenses/by/4.0/
- DOI
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- 10.3390/cells12141868
- 公開者
- MDPI AG
説明
<jats:p>The mammalian Ccr4–Not complex, carbon catabolite repression 4 (Ccr4)-negative on TATA-less (Not), is a large, highly conserved, multifunctional assembly of proteins that acts at different cellular levels to regulate gene expression. It is involved in the control of the cell cycle, chromatin modification, activation and inhibition of transcription initiation, control of transcription elongation, RNA export, and nuclear RNA surveillance; the Ccr4–Not complex also plays a central role in the regulation of mRNA decay. Growing evidence suggests that gene transcription has a vital role in shaping the landscape of genome replication and is also a potent source of replication stress and genome instability. Here, we have examined the effects of the inactivation of the Ccr4–Not complex, via the depletion of the scaffold subunit CNOT1, on DNA replication and genome integrity in mammalian cells. In CNOT1-depleted cells, the elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which, together with R-loop accumulation, results in replication fork slowing, DNA damage, and senescence. Furthermore, we have shown that the stability of TBP mRNA increases in the absence of CNOT1, which may explain its elevated protein expression in CNOT1-depleted cells. Finally, we have shown the activation of mitogen-activated protein kinase signalling as evidenced by ERK1/2 phosphorylation in the absence of CNOT1, which may be responsible for the observed cell cycle arrest at the border of G1/S.</jats:p>
収録刊行物
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- Cells
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Cells 12 (14), 1868-, 2023-07-17
MDPI AG
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キーワード
詳細情報 詳細情報について
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- CRID
- 1360021391887302912
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- ISSN
- 20734409
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- 資料種別
- journal article
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- データソース種別
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- Crossref
- KAKEN
- OpenAIRE
