<i>Drosophila</i> Bag-of-marbles directly interacts with the CAF40 subunit of the CCR4–NOT complex to elicit repression of mRNA targets

Sgromo, Annamaria; Raisch, Tobias; Backhaus, Charlotte; Keskeny, Csilla; Alva, Vikram; Weichenrieder, Oliver; Izaurralde, Elisa

doi:10.1261/rna.064584.117

Cited by 45 publications

(65 citation statements)

References 43 publications

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“…Importantly, the very same surface of CAF40 was described previously to be engaged also by the CBMs of Roquin and Bam ( Fig. 4E,F; Sgromo et al 2017Sgromo et al , 2018. These CBMs also fold into amphipathic helices, covering surface areas of 841 Å 2 and 748 Å 2 , respectively, and excluding any simultaneous associations of multiple CBMs with CAF40.…”

Section: Alignments Of Not4 Proteins Reveal Highly Conserved Sequencesupporting

confidence: 71%

“…The NOT module provides binding sites for Bicaudal-C (Chicoine et al 2007), Nanos (Bhandari et al 2014;Raisch et al 2016), and Roquin (Sgromo et al 2017). CAF40 is known to be contacted by Roquin (Sgromo et al 2017), Bag of marbles (Bam) (Sgromo et al 2018), and TTP (Bulbrook et al 2018) as well as the GW182/TNRC6 family of proteins that mediates microRNA-mediated mRNA repression and decay (Chen et al 2014;Mathys et al 2014).…”

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confidence: 99%

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A conserved CAF40-binding motif in metazoan NOT4 mediates association with the CCR4–NOT complex

et al. 2019

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The multisubunit CCR4-NOT mRNA deadenylase complex plays important roles in the posttranscriptional regulation of gene expression. The NOT4 E3 ubiquitin ligase is a stable component of the CCR4-NOT complex in yeast but does not copurify with the human or Drosophila melanogaster complex. Here we show that the C-terminal regions of human and D. melanogaster NOT4 contain a conserved sequence motif that directly binds the CAF40 subunit of the CCR4-NOT complex (CAF40-binding motif [CBM]). In addition, nonconserved sequences flanking the CBM also contact other subunits of the complex. Crystal structures of the CBM-CAF40 complex reveal a mutually exclusive binding surface for NOT4 and Roquin or Bag of marbles mRNA regulatory proteins. Furthermore, CAF40 depletion or structure-guided mutagenesis to disrupt the NOT4-CAF40 interaction impairs the ability of NOT4 to elicit decay of tethered reporter mRNAs in cells. Together with additional sequence analyses, our results reveal the molecular basis for the association of metazoan NOT4 with the CCR4-NOT complex and show that it deviates substantially from yeast. They mark the NOT4 ubiquitin ligase as an ancient but nonconstitutive cofactor of the CCR4-NOT deadenylase with potential recruitment and/or effector functions.

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Section: Alignments Of Not4 Proteins Reveal Highly Conserved Sequencesupporting

confidence: 71%

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confidence: 99%

A conserved CAF40-binding motif in metazoan NOT4 mediates association with the CCR4–NOT complex

et al. 2019

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“…Recruitment of CNOT by RNA-binding factors has emerged as an important mechanism of posttranscriptional regulation (39,45,(77)(78)(79)(80). Utilization of CNOT by Pum orthologs has been reported in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans, Drosophila melanogaster and mammals (11,43,44,72,(81)(82)(83), and thus represents an evolutionarily conserved mechanism.…”

Section: Discussionmentioning

confidence: 99%

Unique repression domains of Pumilio utilize deadenylation and decapping factors to accelerate destruction of target mRNAs

Arvola

Chang

Buytendorp

et al. 2019

Preprint

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Pumilio is an RNA-binding protein that represses a network of mRNAs to control embryogenesis, stem cell fate, fertility, and neurological functions in Drosophila. We sought to identify the mechanism of Pumilio-mediated repression and find that it accelerates degradation of target mRNAs, mediated by three N-terminal Repression Domains (RDs), which are unique to Pumilio orthologs. We show that the repressive activities of the Pumilio RDs depend on specific subunits of the Ccr4-Not (CNOT) deadenylase complex. Depletion of Pop2, Not1, Not2, or Not3 subunits alleviates Pumilio RD-mediated repression of protein expression and mRNA decay, whereas depletion of other CNOT components had little or no effect. Moreover, the catalytic activity of Pop2 deadenylase is important for Pumilio RD activity. Further, we show that the Pumilio RDs directly bind to the CNOT complex. We also report that the decapping enzyme, Dcp2, participates in repression by the N-terminus of Pumilio. These results support a model wherein Pumilio utilizes CNOT deadenylase and decapping complexes to accelerate destruction of target mRNAs. Because the N-terminal RDs are conserved in mammalian Pumilio orthologs, the results of this work broadly enhance our understanding of Pumilio function and roles in diseases including cancer, neurodegeneration, and epilepsy.

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“…Thus, one possible model is that Bam/Otu creates an intrinsic timer in dividing cysts by stabilizing CycA in cystoblasts and 2-cell cysts, promoting subsequent APC/C activity and destruction of CycA in 4and 8-cell cysts, triggering the terminal mitotic division. The Bam/Otu timer could be reinforced by other mechanisms that either activate the APC/C, such as Gcn5-induced acetylation , or regulate CycA levels, such as reduction of CycA mRNA by the CCR4-NOT deadenylase complex (Morris et al, 2005;Fu et al, 2015;Sgromo et al, 2018) and the translational repressor Bruno (Sugimura and Lilly, 2006).…”

Section: An Intrinsic Timer Likely Regulates Fusome-orchestrated Mitomentioning

confidence: 99%

Coordinating Proliferation, Polarity, and Cell Fate in the Drosophila Female Germline

Hinnant

Merkle

Ables

2020

Front. Cell Dev. Biol.

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Gametes are highly specialized cell types produced by a complex differentiation process. Production of viable oocytes requires a series of precise and coordinated molecular events. Early in their development, germ cells are an interconnected group of mitotically dividing cells. Key regulatory events lead to the specification of mature oocytes and initiate a switch to the meiotic cell cycle program. Though the chromosomal events of meiosis have been extensively studied, it is unclear how other aspects of oocyte specification are temporally coordinated. The fruit fly, Drosophila melanogaster, has long been at the forefront as a model system for genetics and cell biology research. The adult Drosophila ovary continuously produces germ cells throughout the organism's lifetime, and many of the cellular processes that occur to establish oocyte fate are conserved with mammalian gamete development. Here, we review recent discoveries from Drosophila that advance our understanding of how early germ cells balance mitotic exit with meiotic initiation. We discuss cell cycle control and establishment of cell polarity as major themes in oocyte specification. We also highlight a germline-specific organelle, the fusome, as integral to the coordination of cell division, cell polarity, and cell fate in ovarian germ cells. Finally, we discuss how the molecular controls of the cell cycle might be integrated with cell polarity and cell fate to maintain oocyte production.

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Drosophila Bag-of-marbles directly interacts with the CAF40 subunit of the CCR4–NOT complex to elicit repression of mRNA targets

Cited by 45 publications

References 43 publications

A conserved CAF40-binding motif in metazoan NOT4 mediates association with the CCR4–NOT complex

A conserved CAF40-binding motif in metazoan NOT4 mediates association with the CCR4–NOT complex

Unique repression domains of Pumilio utilize deadenylation and decapping factors to accelerate destruction of target mRNAs

Coordinating Proliferation, Polarity, and Cell Fate in the Drosophila Female Germline

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