Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain

Skariah, Geena; Seimetz, Joseph; Norsworthy, Miles D; Lannom, Monica C.; Kenny, Phillip J.; Elrakhawy, Mohamed; Forsthoefel, Craig; Drnevich, Jenny; Kalsotra, Auinash; Ceman, Stephanie

doi:10.1186/s12915-017-0387-1

Cited by 42 publications

(77 citation statements)

References 67 publications

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“…Following transcription in the nucleus, L1 mRNA is exported to the cytoplasm where translation of the L1-encoded proteins occurs. L1 mRNAs face MOV10, which had been shown in several independent studies to be a potent restriction factor of retrotransposition ( Arjan-Odedra et al., 2012 , Choi et al., 2018 , Goodier et al., 2012 , Li et al., 2013 , Lu et al., 2012 , Skariah et al., 2017 ). Despite efficient production of L1-ORF1p, newly synthesized L1-ORF1p is likely in constant kinetic competition with MOV10 ( Naufer et al., 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, the mechanism of the latter is not clear. Even for the well-established retrotransposition and retrovirus restriction factor, the RNA helicase MOV10 ( Arjan-Odedra et al., 2012 , Choi et al., 2018 , Goodier et al., 2012 , Li et al., 2013 , Lu et al., 2012 , Skariah et al., 2017 ), the exact mechanisms of action remain to be clarified.…”

Section: Introductionmentioning

confidence: 99%

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Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s

Warkocki

Krawczyk

Adamska

et al. 2018

Cell

104

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SummaryLINE-1 retrotransposition is tightly restricted by layers of regulatory control, with epigenetic pathways being the best characterized. Looking at post-transcriptional regulation, we now show that LINE-1 mRNA 3′ ends are pervasively uridylated in various human cellular models and in mouse testes. TUT4 and TUT7 uridyltransferases catalyze the modification and function in cooperation with the helicase/RNPase MOV10 to counteract the RNA chaperone activity of the L1-ORF1p retrotransposon protein. Uridylation potently restricts LINE-1 retrotransposition by a multilayer mechanism depending on differential subcellular localization of the uridyltransferases. We propose that uridine residues added by TUT7 in the cytoplasm inhibit initiation of reverse transcription of LINE-1 mRNAs once they are reimported to the nucleus, whereas uridylation by TUT4, which is enriched in cytoplasmic foci, destabilizes mRNAs. These results provide a model for the post-transcriptional restriction of LINE-1, revealing a key physiological role for TUT4/7-mediated uridylation in maintaining genome stability.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s

Warkocki

Krawczyk

Adamska

et al. 2018

Cell

104

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“…Therefore, MOV10 has been implicated in facilitating sequestration of L1 ribonucleoproteins (RNPs) and a degradation of L1 RNAs ( 15 ). On the other hand, several studies have highlighted diverse functions of nuclear MOV10 ( 22 ), including suppression of retroelements ( 17 ). Hence, the exact mode of MOV10-mediated L1 restriction remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition

Choi

Hwang

Ahn

2018

Nucleic Acids Research

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Long interspersed nuclear element 1 is an autonomous non-long terminal repeat retrotransposon that comprises ∼17% of the human genome. Its spontaneous retrotransposition and the accumulation of heritable L1 insertions can potentially result in genome instability and sporadic disorders. Moloney leukemia virus 10 homolog (MOV10), a putative RNA helicase, has been implicated in inhibiting L1 replication, although its underlying mechanism of action remains obscure. Moreover, the physiological relevance of MOV10-mediated L1 regulation in human disease has not yet been examined. Using a proteomic approach, we identified RNASEH2 as a binding partner of MOV10. We show that MOV10 interacts with RNASEH2, and their interplay is crucial for restricting L1 retrotransposition. RNASEH2 and MOV10 co-localize in the nucleus, and RNASEH2 binds to L1 RNAs in a MOV10-dependent manner. Small hairpin RNA-mediated depletion of either RNASEH2A or MOV10 results in an accumulation of L1-specific RNA-DNA hybrids, suggesting they contribute to prevent formation of vital L1 heteroduplexes during retrotransposition. Furthermore, we show that RNASEH2-MOV10-mediated L1 restriction downregulates expression of the rheumatoid arthritis-associated inflammatory cytokines and matrix-degrading proteinases in synovial cells, implicating a potential causal relationship between them and disease development in terms of disease predisposition.

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“…All these studies indicate that it is not miRNA alone, but the composition of miRISC has a great significance in the pathophysiology of disorders of the nervous system. There is Bhattacharyya, 2016, 2018) FMRP (Castren et al, 2005;Tervonen et al, 2009;Callan et al, 2010;Saffary and Xie, 2011;Jeon et al, 2014) TRIM-32 (Brat, mei-P26,NHL-2) (Bello, 2006;Betschinger et al, 2006;Lee et al, 2006;Bowman et al, 2008;Neumüller et al, 2008;Hammell et al, 2009;Schwamborn et al, 2009;Loewen et al, 2018) Hu Proteins (Marusich et al, 1994;Dobashi et al, 1998;Kasashima et al, 1999;Anderson et al, 2000;Akamatsu et al, 2002Akamatsu et al, , 2005Perrone-Bizzozero and Bolognani, 2002;Kraushar et al, 2014) Pumilio (Burow et al, 2015;Zahr et al, 2018) ESCRT Factors FMRP (Dockendorff et al, 2002;Ivanco and Greenough, 2002;Morales et al, 2002;Michel, 2004;Pan et al, 2004;Li, 2009;Doll and Broadie, 2015;Wang et al, 2015;Zimmer et al, 2017;Shen et al, 2019) MOV10 (Skariah et al, 2017) Pumilio (Menon et al, 2004(Menon et al, , 2009Ye et al, 2004;Vessey et al, 2010;...…”

Section: Discussionmentioning

confidence: 99%

The Role of Dynamic miRISC During Neuronal Development

Nawalpuri

Ravindran

Muddashetty

2020

Front. Mol. Biosci.

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Activity-dependent protein synthesis plays an important role during neuronal development by fine-tuning the formation and function of neuronal circuits. Recent studies have shown that miRNAs are integral to this regulation because of their ability to control protein synthesis in a rapid, specific and potentially reversible manner. miRNA mediated regulation is a multistep process that involves inhibition of translation before degradation of targeted mRNA, which provides the possibility to store and reverse the inhibition at multiple stages. This flexibility is primarily thought to be derived from the composition of miRNA induced silencing complex (miRISC). AGO2 is likely the only obligatory component of miRISC, while multiple RBPs are shown to be associated with this core miRISC to form diverse miRISC complexes. The formation of these heterogeneous miRISC complexes is intricately regulated by various extracellular signals and cell-specific contexts. In this review, we discuss the composition of miRISC and its functions during neuronal development. Neurodevelopment is guided by both internal programs and external cues. Neuronal activity and external signals play an important role in the formation and refining of the neuronal network. miRISC composition and diversity have a critical role at distinct stages of neurodevelopment. Even though there is a good amount of literature available on the role of miRNAs mediated regulation of neuronal development, surprisingly the role of miRISC composition and its functional dynamics in neuronal development is not much discussed. In this article, we review the available literature on the heterogeneity of the neuronal miRISC composition and how this may influence translation regulation in the context of neuronal development.

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Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain

Cited by 42 publications

References 67 publications

Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s

Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s

Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition

The Role of Dynamic miRISC During Neuronal Development

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