Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability
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 modific...
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MDPI AG
2023-07-01
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| author | Nafiseh Chalabi Hagkarim Morteza Chalabi Hajkarim Toru Suzuki Toshinobu Fujiwara G. Sebastiaan Winkler Grant S. Stewart Roger J. Grand |
| author_facet | Nafiseh Chalabi Hagkarim Morteza Chalabi Hajkarim Toru Suzuki Toshinobu Fujiwara G. Sebastiaan Winkler Grant S. Stewart Roger J. Grand |
| author_sort | Nafiseh Chalabi Hagkarim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T01:13:06Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T01:13:06Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e0dd40c751b44c6286d661ede3c221a52023-11-18T18:46:19ZengMDPI AGCells2073-44092023-07-011214186810.3390/cells12141868Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome InstabilityNafiseh Chalabi Hagkarim0Morteza Chalabi Hajkarim1Toru Suzuki2Toshinobu Fujiwara3G. Sebastiaan Winkler4Grant S. Stewart5Roger J. Grand6Institute for Cancer and Genomic Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UKDepartment of Medicine Haematology & Oncology, Columbia University, New York City, NY 10032, USADivision of RNA and Gene Regulation, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanLaboratory of Biochemistry, Kindai University, Higashi-Osaka City 577-8502, JapanSchool of Pharmacy, University of Nottingham, Nottingham NG7 3RD, UKInstitute for Cancer and Genomic Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UKInstitute for Cancer and Genomic Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UKThe 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.https://www.mdpi.com/2073-4409/12/14/1868CNOT complexCNOT1CNOT7CNOT8genome instabilityDNA repair |
| spellingShingle | Nafiseh Chalabi Hagkarim Morteza Chalabi Hajkarim Toru Suzuki Toshinobu Fujiwara G. Sebastiaan Winkler Grant S. Stewart Roger J. Grand Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability Cells CNOT complex CNOT1 CNOT7 CNOT8 genome instability DNA repair |
| title | Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability |
| title_full | Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability |
| title_fullStr | Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability |
| title_full_unstemmed | Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability |
| title_short | Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability |
| title_sort | disruption of the mammalian ccr4 not complex contributes to transcription mediated genome instability |
| topic | CNOT complex CNOT1 CNOT7 CNOT8 genome instability DNA repair |
| url | https://www.mdpi.com/2073-4409/12/14/1868 |
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