The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

Abstract

nature structural & molecular biology advance online publication a r t i c l e sAlthough undisputable evidence has clearly demonstrated that the nuclear steps of mRNA processing are mechanistically linked to transcription, a conceptual evolution in gene regulation has come with the realization that transcription might also be functionally connected to more remote processes occurring in the cytoplasm, such as mRNA decay 1,2 . Cytoplasmic mRNA decay is initiated by deadenylation, a rate-limiting event during which the poly(A) tail of the transcript is trimmed off by the CCR4-NOT complex, the main deadenylation machinery in eukaryotes 3 . The degradation of specific mRNAs, a key process in the regulation of eukaryotic gene expression, is achieved through the recruitment of the CCR4-NOT complex by sequence-specific RNA-binding proteins (RBPs) or by the microRNA machinery 3,4 . Poly(A)-shortened mRNAs, along with factors involved in the deadenylation, decapping and mRNA-degradation machineries, accumulate in microscopic mRNA-protein complex (mRNP) aggregates called processing bodies (PBs) 5 .The idea of coupling between mRNA synthesis and degradation has recently emerged. Genome-wide expression studies in yeast have shown that mRNA synthesis and decay are mechanistically and functionally coordinated, thus supporting the existence of common molecular effectors [6][7][8][9] . In particular, the CCR4-NOT deadenylation complex was first described as a transcriptional regulator and has been implicated in initiation and elongation by RNA polymerase II 10,11 . More surprisingly, it has also been shown that degradation of yeast mRNAs is determined by cis-acting sequence elements in promoters 12,13 . These findings have led to the concept of mRNA imprinting, in which sequence-specific DNA-binding factors might orchestrate mRNA synthesis and decay. This decay would occur via loading of factors regulating cytoplasmic mRNA degradation onto the transcribing mRNA 14 . However, the identity of these DNA-binding mRNA coordinators is still obscure, and it remains to be tested whether such coupling between transcription and decay also exists in higher eukaryotes. E26 (Ets) proteins, a family of 28 helix-loop-helix transcription factors (TFs) in metazoans, are characterized by a highly conserved DNA-binding ETS domain 15 . Through this domain, Ets factors bind specific gene promoters and act as key regulators in many biological processes including cellular proliferation, apoptosis, differentiation and survival 16 . ERG, FLI1 and the more structurally divergent FEV compose the Erg subfamily of Ets factors and have been identified as driving factors in prostate cancer, Ewing's tumors and leukemias 15,17 . Using ERG as a paradigm, we sought to investigate the possibility that eukaryotic transcription factors might be directly involved in cytoplasmic mRNA decay. We demonstrate that ERG triggers degradation of mRNAs connected to Aurora signaling by recruiting RBPs and the CCR4-NOT deadenylation complex and that this activity is important fo...

A heterozygous, intragenic deletion of CNOT2 recapitulates the phenotype of 12q15 deletion syndrome

“…CNOT2 encodes a subunit of the multi-component CCR4-NOT complex, involved in gene expression regulating mRNA synthesis, degradation, splicing, transport, and localization (Jeong, Kwon, Jeong, Sohn, & Kim, 2017;Rambout et al, 2016). According to its wide biological functions, it is ubiquitously expressed (https://www.genecards.org),…”

The CCR4-NOT complex contributes to repression of Major Histocompatibility Complex class II transcription

“…Indirect effects of CNOT-mediated transcriptional repression could involve the association or regulation of transcription factors. Examples for such a mechanism are interactions of CNOT1 with estrogen receptor α, CNOT9 binding to c-Myb 20 and CNOT2 interaction with ERG 60 .…”

PERIOD-controlled deadenylation of the timeless transcript in the Drosophila circadian clock

“…Although a new transcription-independent role of PER cannot be excluded, different mechanisms have been revealed that link transcription with the control of mRNA polyadenylation and stability (48,49). Notably, interactions between the transcription machinery and the CCR4-NOT complex indicate that mRNA deadenylation can be regulated at the transcriptional level (50)(51)(52)(53), raising the possibility that PER might interfere with POP2 activity through its role as a transcriptional repressor. For example, CBP/p300 acetylates CAF1 to promote its activity (52).…”