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Molecular and biological functions of TRIM‐NHL RNA‐binding proteins

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Abstract The TRIM‐NHL family of proteins shares a conserved domain architecture and play crucial roles in stem cell biology, fertility, and development. This review synthesizes new insights that have revolutionized our understanding of the molecular and biological functions of TRIM‐NHL proteins. Multiple TRIM‐NHLs have been shown to bind specific RNA sequences and structures. X‐ray crystal structures of TRIM‐NHL proteins in complex with RNA ligands reveal versatile modes of RNA recognition by the NHL domain. Functional and genetic analyses show that TRIM‐NHL RNA‐binding proteins negatively regulate the protein expression from the target mRNAs that they bind. This repressive activity plays a crucial role in controlling stem cell fate in the developing brain and differentiating germline. To highlight these paradigms, we focus on several of the most‐extensively studied TRIM‐NHL proteins, specifically Drosophila and vertebrate TRIM71, among others. Brat is essential for development and regulates key target mRNAs to control differentiation of germline and neural stem cells. TRIM71 is also required for development and promotes stem cell proliferation while antagonizing differentiation. Moreover, TRIM71 can be utilized to help reprogram fibroblasts into induced pluripotent stem cells. Recently discovered mutations in TRIM71 cause the neurodevelopmental disease congenital hydrocephalus and emphasize the importance of its RNA‐binding function in brain development. Further relevance of TRIM71 to disease pathogenesis comes from evidence linking it to several types of cancer, including liver and testicular cancer. Collectively, these advances demonstrate a primary role for TRIM‐NHL proteins in the post‐transcriptional regulation of gene expression in crucial biological processes. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications Translation > Translation Regulation RNA Turnover and Surveillance > Regulation of RNA Stability
Structure and phylogeny of TRIM‐NHL proteins. (a) Architecture of a generalized TRIM‐NHL protein and arrangement of conserved domains, including several that are variable within family members. (b) Cladogram of TRIM‐NHL family, based on generated and published phylogenies. For generated phylogeny, all annotated full‐length coding sequences of TRIM‐NHL proteins were aligned using ClustalW, and Maximum Likelihood phylogeny prepared using MEGAX. Species: Drosophila melanogaster (Dm), Caenorhabditis elegans (Ce), Xenopus laevis (Xl), Danio rerio (Dr), Gallus gallus (Gg), Mus musculus (Mm), Homo sapiens (Hs). (c) X‐ray crystal structure (PDB: 1Q7F) of the Brat NHL domain (Edwards, Wilkinson, Wharton, & Aggarwal, 2003). The coloration highlights the individual NHL repeats
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TRIM‐NHL proteins control nucleolar size in Drosophila and C. elegans. (a) Drosophila Brat and Mei‐P26 repress myc expression, which controls expression of rRNA and ribosome biogenesis factors to affect nucleolar size, particularly wing imaginal discs. (b) C. elegans NCL‐1 represses the FIB‐1 mRNA to control nucleolar size
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Brat and Mei‐P26 regulate Drosophila oogenesis. (a) Early oogenesis in adult Drosophila. Germline stem cells (GSCs), in contact with somatic cap cells, receive Decapentaplegic (Dpp) signal that is necessary for their maintenance. The resulting signaling cascade ensures expression of Nanos (N), Pumilio (P), and Mei‐P26 (M). Asymmetric cell division pushes one daughter cell below the signal threshold (dashed line), causing expression of Bam (B) and Brat. The nascent cystoblast (CB) further divides incompletely into cysts, one of which is designated to become the oocyte (Ooc). (b) Molecular pathways maintaining GSC identity. Dpp signaling promotes Mothers against Dpp (Mad)‐mediated transcriptional (Tx) regulation of bag of marbles (bam)L) of brat mRNA. (c) Molecular pathways promoting differentiation of nascent cystoblasts. Loss of Dpp signal in the cystoblast allows expression of Bam. In turn, Bam collaborates with Mei‐P26, Sex‐lethal (Sxl), and Benign gonial cell neoplasm (Bgcn) proteins to repress translation of nanos mRNA. As a result, translational repression of Brat is alleviated. Brat protein collaborates with Pum to repress expression of Mad, Media and schnurri (shn) transcription factors. Dotted lines represent reduced strength of interactions
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Brat regulates neurogenesis. (a) Brat controls early differentiation of Drosophila Type II neuroblasts in the larval brain. During asymmetric cell division, Miranda (Mira) localizes and concentrates Brat in the nascent Intermediate Neural Progenitor (INP). Following cytokinesis, Mira is degraded, releasing Brat. During INP maturation, Brat is reduced and transcription factors Asense and Deadpan are expressed. These transcription factors promote further asymmetric divisions of INPs, forming glial cells and neurons. (b) Proposed RNA‐dependent and –independent regulatory roles of Brat in INP maturation. Activation is indicated by pointed arrows whereas repression is marked with blunted arrows. Observed physical associations of Brat with the RNA‐binding protein Tis11 and CNOT deadenylase complex are marked with bulb‐end lines. Translational control (TL) and transcriptional control (TX) are indicated on the respective arrows
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Structure of Drosophila melanogaster Brat NHL domain bound to RNA. (a) Positively charged channel on the top, RNA‐binding surface of Brat NHL domain (PDB: 1Q7F) (Edwards et al., 2003). The surface charge is visualized with Adaptive Poisson‐Boltzmann Solver (APBS) macromolecular electrostatics calculation plugin in PyMOL. Blue denotes positive charge, red denotes negative charge. (b) Structure of the Brat NHL domain in complex with its RNA binding site from the hunchback mRNA 3′UTR (PDB: 4ZLR) (Loedige et al., 2015). The linear chain of nucleotides contact side chains of loop residues on the NHL surface. (c) Brat (and NCL‐1) consensus binding motif consists of a core 5′‐UGUU, with variable flanking nucleotides: H = (A/C/U), D = (A/G/U). The Brat binding motif consensus is derived from Loedige et al. (2015) and Laver et al. (2015)
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Brat regulates translation of hunchback mRNA during early embryogenesis. (a) Gradients of key maternal mRNAs and proteins in the early Drosophila embryo control polarity of the body plan. Hunchback mRNA is ubiquitous, but Hunchback protein is restricted to the anterior half, mediated by translational repression by the combination of Brat, Pum, and Nanos. Pum and Brat protein are distributed throughout the embryo, whereas Nanos protein forms a gradient emanating from the posterior. (b) Model of translational repression mechanism by Brat, Pum, and Nanos. The poly(A)‐tail of hunchback mRNA is shortened the CNOT deadenylase, which can be recruited by the three RNA‐binding proteins bound to the 3′UTR. Brat can also utilize the 5′ 7‐methyl guanosine (m7G) cap binding protein, 4EHP, to repress translation initiation
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Structure of Danio rerio Trim71 NHL domain bound to RNA. (a) The positively charged cavity on the top surface of Dr Trim71 NHL domain (PDB: 6FPT) (Kumari et al., 2018) was visualized with APBS in PyMOL. Blue denotes positive charge, red denotes negative charge. (b) X‐ray crystal structure of the Dr Trim71 NHL domain in complex with the RNA‐binding site from the 3′UTR of the mab‐10 mRNA (PDB: 6FQL) (Kumari et al., 2018). The RNA stem loop binding site sits within an indentation on the Trim71 NHL domain. Nucleotides that are important for RNA‐binding specificity are highlighted in color. (c) The LIN‐41 consensus binding motif consists of a short stem with a three nucleotide loop. Specific nucleotides in the loop (position III) and stem (positions −1 & +1) are preferred by LIN‐41 and Trim71 orthologs
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RNA Turnover and Surveillance > Regulation of RNA Stability
Translation > Translation Regulation
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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