The Ccr4‐Not complex is a key regulator of eukaryotic gene expression

Abstract

The Ccr4‐Not complex is a multisubunit complex present in all eukaryotes that contributes to regulate gene expression at all steps, from production of messenger RNAs (mRNAs) in the nucleus to their degradation in the cytoplasm. In the nucleus it influences the post‐translational modifications of the chromatin template that has to be remodeled for transcription, it is present at sites of transcription and associates with transcription factors as well as with the elongating polymerase, it interacts with the factors that prepare the new transcript for export to the cytoplasm and finally is important for nuclear quality control and influences mRNA export. In the cytoplasm it is present in polysomes where mRNAs are translated and in RNA granules where mRNAs will be redirected upon inhibition of translation. It influences mRNA translatability, and is needed during translation, on one hand for co‐translational protein interactions and on the other hand to preserve translation that stalls. It is one of the relevant players during co‐translational quality control. It also interacts with factors that will repress translation or induce mRNA decapping when recruited to the translating template. Finally, Ccr4‐Not carries deadenylating enzymes and is a key player in mRNA decay, generic mRNA decay that follows normal translation termination, co‐translational mRNA decay of transcripts on which the ribosomes stall durably or which carry a non‐sense mutation and finally mRNA decay that is induced by external signaling for a change in genetic programming. Ccr4‐Not is a master regulator of eukaryotic gene expression. WIREs RNA 2016, 7:438–454. doi: 10.1002/wrna.1332For further resources related to this article, please visit the WIREs website.

Accumulation of RNA on chromatin disrupts heterochromatic silencing

“…It remains to be analyzed why specific RNAs are degraded on chromatin and others in the soluble fraction. The Ccr4-Not complex is found in the cytosol and the nucleus (Collart 2016), and our data suggest that Ccr4-Not localization might be a result of RNA localization.…”

Proteomic analysis of the gamma human papillomavirus type 197 E6 and E7 associated cellular proteins

“…This complex importantly regulates many aspects of mRNA metabolism in the nucleus as well as in the cytoplasm, including transcriptional initiation and elongation, nuclear RNA processing and export as well as co-translational quality control. In addition some studies have implicated this complex in the regulation of histone modifications, particularly trimethylation of histone H3 at lysine 4 (H3K4me) (Collart, 2016; Miller and Reese, 2012). …”

Reconstitution of Targeted Deadenylation by the Ccr4-Not Complex and the YTH Domain Protein Mmi1

“…It influences transcription, mRNA stability, and translation (Collart, 2016), playing important roles in numerous cellular pathways including cell cycle, early development, inflammation, and neuronal processes (Beilharz and Preiss, 2007, Lackner et al., 2007, Weill et al., 2012). Ccr4-Not possesses exonuclease activity that shortens the poly(A) tail found at the 3′ end of almost every eukaryotic mRNA, a process called deadenylation (Tucker et al., 2001).…”

“…Ccr4-Not contains seven core subunits, including two exonucleases, Caf1 (also called Pop2, CNOT7, or CNOT8) and Ccr4 (also called CNOT6 or CNOT6L) (Collart, 2016, Tucker et al., 2001, Wahle and Winkler, 2013) (Figure 1A). Caf1 and Ccr4 interact with each other directly (Basquin et al., 2012), but the relevance of two different nucleases within the complex is unclear.…”