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Unwinding the roles of RNA helicase MOV10

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Abstract MOV10 is an RNA helicase that associates with the RNA‐induced silencing complex component Argonaute (AGO), likely resolving RNA secondary structures. MOV10 also binds the Fragile X mental retardation protein to block AGO2 binding at some sites and associates with UPF1, a principal component of the nonsense‐mediated RNA decay pathway. MOV10 is widely expressed and has a key role in the cellular response to viral infection and in suppressing retrotransposition. Posttranslational modifications of MOV10 include ubiquitination, which leads to stimulation‐dependent degradation, and phosphorylation, which has an unknown function. MOV10 localizes to the nucleus and/or cytoplasm in a cell type‐specific and developmental stage‐specific manner. Knockout of Mov10 leads to embryonic lethality, underscoring an important role in development where it is required for the completion of gastrulation. MOV10 is expressed throughout the organism; however, most studies have focused on germline cells and neurons. In the testes, the knockdown of Mov10 disrupts proliferation of spermatogonial progenitor cells. In brain, MOV10 is significantly elevated postnatally and binds mRNAs encoding cytoskeleton and neuron projection proteins, suggesting an important role in neuronal architecture. Heterozygous Mov10 mutant mice are hyperactive and anxious and their cultured hippocampal neurons have reduced dendritic arborization. Zygotic knockdown of Mov10 in Xenopus laevis causes abnormal head and eye development and mislocalization of neuronal precursors in the brain. Thus, MOV10 plays a vital role during development, defense against viral infection and in neuronal development and function: its many roles and regulation are only beginning to be unraveled. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications
Evolutionary conservation of MOV10. Amino acid alignment of human (NM_020963.4), rhesus monkey (NM_001261223.1), mouse (NM_008619.2), Xenopus (XM_018246602.1), and zebrafish (NM_001044342.2) are shown beginning at amino acid 83 in Homo sapiens. The conserved cysteine and histidine residues between human, rhesus and mouse that form a consensus CH domain are highlighted in yellow and green, respectively. The helicase motifs are presented in red and annotated according to Fairman‐Williams et al. (2010), Rocak and Linder (2004), X. Wang et al. (2010). Gag‐binding domain is presented based on findings of Abudu et al. (2012). Red exclamation marks represent complete conservation across all five genera, green asterisks indicate strongly similar group conservation; asterisk of blue shades indicate weakly similar group conservation and blanks are regions of no conservation. Alignment was done using ClustalW function in msa package (Bodenhofer et al., 2015)
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Proposed models for the role of MOV10 in inhibition of L1 retrotransposition: (1) L1 mRNA is transcribed by RNA polymerase and the transcript is exported to the cytosol. (2) The L1 mRNA is translated into ORF1P chaperone protein and ORF2P endonuclease/reverse transcriptase and assembled into the L1 RNP. (3) MOV10 binds at the rG4 present in the L1 3′ UTR. TUT4 binds MOV10 and adds U residues at the 3′ end. (4) The complex is taken to the PBs for storage or decay or exported back into the nucleus where L1 retrotransposition suppression is proposed to occur in two ways: (5) at the insertion site, the U residues are not complementary to the target site which results in failure of TPRT (Warkocki et al., 2018). (6) A second model proposed that at the site of insertion, ORF2p which binds to the polyA tail of the L1 mRNA attempts to reverse transcribe the L1 mRNA into cDNA and encounters steric hindrance from MOV10 which is moving in the 5′ to 3′ direction to unwind the rG4 or the DNA:RNA heteroduplexes in association with RNASEH2 (Choi et al., 2018; Skariah et al., 2017). TPRT, target‐primed reverse transcription; UTR, untranslated region
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Role of MOV10 in miRISC pathway and translation regulation in neurons: General biogenesis of miRNA for miRNA‐mediated regulation of target mRNAs. miRNAs are transcribed from the genome after which they are processed through the DROSHA microprocessor complex. After being exported to the cytoplasm, the pre‐miRNA is further processed to remove the hairpin loop structure and yield a double‐stranded miRNA. The miRNA strand gets cleaved, and one strand is loaded onto AGO to form the RISC. RISC‐bound mRNAs are either translationally suppressed by decay or by inhibition. Both the processes involve MOV10 (O'Carroll & Schaefer, 2013). RISC‐bound mRNAs can be transported to RNA condensates like SGs or PBs (Riggs et al., 2020). MOV10 associates with proteins associated with both SGs (G3BP1, FMRP and PABP) and PBs (DCP1 and GW182). In the neurons, mRNAs are stabilized to form mRNPs which are transported along microtubules to the dendritic regions (Zeitelhofer et al., 2008). Here, MOV10 associates with AGO2 and FMRP to regulate mRNA translation. Upon NMDAR stimulation, FMRP is phosphorylated which dissociates AGO2 from the mRNAs to allow local translation (Kenny et al., 2020, 2019). AGO2, Argonaute 2; FMRP, Fragile X mental retardation protein; PBs, processing bodies; RISC, RNA‐induced silencing complex; SGs, stress granules
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MOV10 structure and protein interactors: MOV10 has a putative CH domain near its N‐terminal. The helicase core consisting of seven motifs, is near the C‐terminus. Most known protein interactions occur through the N‐terminus. The MOV10 sequences for interaction with most of the shown proteins are yet to be discovered AGO (Meister et al., 2005); APOBEC3G (C. Liu et al., 2012); TARBP, EIF6, RPL7A, DICER (Chendrimada et al., 2007); UPF1, PABP, ZCCH3, DHX9 (Gregersen et al., 2014); TUT 4 & TUT 7 (Warkocki et al., 2018); ZAP (Taylor et al., 2013); GAG (Abudu et al., 2012); FMRP, FUS (P. J. Kenny et al., 2014, 2020); SHFL (Balinsky et al., 2016); L1 ORF proteins (Goodier et al., 2013; Skariah et al., 2017); RNASEH2 (Choi et al., 2018, p. 20)
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ATP‐dependent helicase activity of MOV10. MOV10 has Walker A and Walker B motifs which allow it to interact and hydrolyze ATP molecules to yield energy for RNA helicase activity. (a) ATP hydrolysis by interactions of the residues with the phosphate group (P) and magnesium ion (Mg2+) are shown (see the text for detail; Caruthers & McKay, 2002). (b) The helicase domains of MOV10 are in OFF configuration. Upon ATP hydrolysis, the domains are in ON configuration and the helicase translocates along the 5′ to 3′ direction to unwind the RNA duplex (Bourgeois et al., 2016)
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes

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