| Autor: |
Hagkarim NC; Institute for Cancer and Genomic Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UK., Hajkarim MC; Department of Medicine Haematology & Oncology, Columbia University, New York City, NY 10032, USA., Suzuki T; Division of RNA and Gene Regulation, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan., Fujiwara T; Laboratory of Biochemistry, Kindai University, Higashi-Osaka City 577-8502, Japan., Winkler GS; School of Pharmacy, University of Nottingham, Nottingham NG7 3RD, UK., Stewart GS; Institute for Cancer and Genomic Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UK., Grand RJ; Institute for Cancer and Genomic Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UK. |
| Jazyk: |
angličtina |
| Zdroj: |
Cells [Cells] 2023 Jul 17; Vol. 12 (14). Date of Electronic Publication: 2023 Jul 17. |
| DOI: |
10.3390/cells12141868 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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