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Vol. 20, Issue 17, 3840-3850, September 1, 2009

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The Ccr4–Not Deadenylase Subunits CNOT7 and CNOT8 Have Overlapping Roles and Modulate Cell Proliferation

Akhmed Aslam^*, Saloni Mittal^*, Frederic Koch, Jean-Christophe Andrau, and G. Sebastiaan Winkler^*

*The School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom; and Centre d'Immunologie de Marseille-Luminy, Université Aix-Marseille, CNRS UMR6102, Institut National de la Santé et de la Recherche Médicale U631, 13288 Marseille, France

Submitted February 20, 2009; Revised June 16, 2009; Accepted July 6, 2009
Monitoring Editor: Marvin Wickens

Accurate gene expression requires the precise control of mRNA levels, which are determined by the relative rates of nuclear (pre-)mRNA synthesis and processing, and cytoplasmic mRNA turnover. A key step in mRNA degradation is the removal of the poly(A) tail, which involves several deadenylases including components of the Ccr4–Not complex. Here, we focused on the role of the human paralogues CNOT7 (hCaf1/Caf1a) and CNOT8 (hPop2/Caf1b/Calif), which possess deadenylase activity mediated by DEDD nuclease domains. We show that efficient proliferation requires both subunits, although combined knockdown of CNOT7 and CNOT8 further reduces cell proliferation indicating partial redundancy between these proteins. Interestingly, the function of CNOT7 in cell proliferation partly depends on its catalytic activity. On the other hand, the interaction between CNOT7 and BTG2, a member of the antiproliferative BTG/Tob family involved in transcription and mRNA decay appears less important for proliferation of MCF7 cells, suggesting that CNOT7 does not function solely in conjunction with BTG2. Further analysis of gene expression profiles of CNOT7 and/or CNOT8 knockdown cells underscores the partial redundancy between these subunits and suggests that regulation of several genes, including repression of the antiproliferative genes MSMB and PMP22, by the Ccr4–Not complex contributes to cell proliferation.

Address correspondence to: G. Sebastiaan Winkler (sebastiaan.winkler{at}nottingham.ac.uk)

Abbreviations used: RT-qPCR, reverse transcriptase-quantitative PCR; BrdU, 5-bromo-2-deoxyuridine.