Nuclear RNA foci from <i>C9ORF72</i> expansion mutation form paraspeckle-like bodies

Česnik, Ana Bajc; Darovic, Simona; Mihevc, Sonja Prpar; Štalekar, Maja; Malnar, Mirjana; Motaln, Helena; Lee, Youn‐Bok; Mazej, Julija; Pohleven, Jure; Grosch, Markus; Modic, Miha; Fonović, Marko; Turk, Boris; Drukker, Micha; Shaw, Christopher E.; Rogelj, Boris

doi:10.1242/jcs.224303

Cited by 42 publications

(32 citation statements)

References 66 publications

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“…Additionally, binding assays ( 80 , 81 ) and systematic evolution of ligands by exponential enrichment (SELEX) ( 82 ) have identified an affinity of NONO for G-rich RNA sequences. Consistent with an affinity for G-rich RNA, several proteomic screens have found NONO among proteins associated with GGGGCC repeat RNA ( 62 , 77 , 102 ). Notably, a mitotic phosphorylation event severely limits the ability of NONO to bind to R-rich RNA but has no effect on binding to G-rich RNA ( 80 ).…”

Section: Discussionmentioning

confidence: 69%

“…The model that NEAT1 G-quadruplexes recruit NONO in seeding paraspeckle assembly is supported by the recent finding ( 102 ) that GGGGCC repeat RNA can act as a functional substitute for NEAT1, inducing formation of paraspeckle-like bodies independent of NEAT1. This seeding activity of GGGGCC repeat RNA provides an opportunity to better understand the properties which imbue an RNA species with this activity.…”

Section: Discussionmentioning

confidence: 78%

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G-quadruplexes offer a conserved structural motif for NONO recruitment to NEAT1 architectural lncRNA

Simko

Liu

Zhang

et al. 2020

Nucleic Acids Research

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The long non-coding RNA NEAT1 serves as a scaffold for the assembly of paraspeckles, membraneless nuclear organelles involved in gene regulation. Paraspeckle assembly requires NEAT1 recruitment of the RNA-binding protein NONO, however the NEAT1 elements responsible for recruitment are unknown. Herein we present evidence that previously unrecognized structural features of NEAT1 serve an important role in these interactions. Led by the initial observation that NONO preferentially binds the G-quadruplex conformation of G-rich C9orf72 repeat RNA, we find that G-quadruplex motifs are abundant and conserved features of NEAT1. Furthermore, we determine that NONO binds NEAT1 G-quadruplexes with structural specificity and provide evidence that G-quadruplex motifs mediate NONO-NEAT1 association, with NONO binding sites on NEAT1 corresponding largely to G-quadruplex motifs, and treatment with a G-quadruplex-disrupting small molecule causing dissociation of native NONO-NEAT1 complexes. Together, these findings position G-quadruplexes as a primary candidate for the NONO-recruiting elements of NEAT1 and provide a framework for further investigation into the role of G-quadruplexes in paraspeckle formation and function.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 78%

G-quadruplexes offer a conserved structural motif for NONO recruitment to NEAT1 architectural lncRNA

Simko

Liu

Zhang

et al. 2020

Nucleic Acids Research

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“…Empty WT and mutant integrin β1/pLVX-AcGFP-N1 plasmids and ecto-tag-integrin β1 plasmid (provided by D.A. Calderwood, Yale University) were transfected into MDA-MB-231 cells using a lentiviral system as previously described [1,28]. Briefly, constructed lentiviral vectors, along with pMD2.G and psPAX2 (Addgene; Cambridge, MA, USA), were packed into HEK293T cells.…”

Section: Stable Transfection Of Wt or Mutant Integrin β1mentioning

confidence: 99%

Role of Site-Specific Glycosylation in the I-Like Domain of Integrin β1 in Small Extracellular Vesicle-Mediated Malignant Behavior and FAK Activation

Cao

Wang

et al. 2021

IJMS

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Integrin β1 plays an essential role in the crosstalk between tumor cells and their microenvironment. Aberrant N-glycosylation of integrin β1 was documented to alter integrin β1 expression, dimerization, and biological function. However, the biological function of site-specific N-glycosylation of integrin β1 on extracellular vesicles is not fully understood. In this study, we mutated putative N-glycosylation sites in different domains of integrin β1. Removal of the N-glycosylation sites on the I-like domain of integrin β1 (termed the Δ4–6 β1 mutant) suppressed focal adhesion kinase (FAK) signaling, cell migration, and adhesion compared with other β1 mutants. Cell adhesion, migration, and activation of FAK were suppressed in recipient MCF7 cells co-cultured with Δ4–6 mutant cells and treated with small extracellular vesicles (sEVs) from Δ4–6 mutant cells. Notably, the wild-type and β1 mutant were both present in sEVs, and could be transferred to recipient cells via sEVs, resulting in changes of cell behavior. Our findings demonstrate the important roles of N-glycosylation of the I-like domain of integrin β1. Moreover, the vesicular Δ4–6 β1 mutant can regulate integrin-mediated functions in recipient cells via sEVs.

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“…This evidence allows to speculate that, considering that FUS and NONO are both required to set up paraspeckles, the formation of paraspeckles is disrupted in FUS mutated ALS patients. Also aberrant nuclear RNA foci formed by the expanded C9ORF72 repeats sequester paraspeckle proteins including TDP-43 [72]. MALAT1 is abundantly expressed and evolutionarily conserved lncRNA.…”

Section: Dysfunctions In Rna Metabolism and Lncrnamentioning

confidence: 99%

RNA Metabolism and Therapeutics in Amyotrophic Lateral Sclerosis

Pansarasa¹,

Gagliardi²,

Sproviero³

et al. 2020

Amyotrophic Lateral Sclerosis - Recent Advances and Therapeutic Challenges

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Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder characterized by the selective death of upper and lowers motor neurons in spinal cord, brain stem, and motor cortex, which leads to paralysis and death within 2-3 years of onset. Deeply sequencing technologies, to simultaneously analyze the transcriptional expression of thousands of genes, offered new possibilities to focus on ALS pathogenesis and, most notably, to find new potential targets for novel treatments. The present book chapter illustrates recent advances in transcriptomic studies in animal models and human samples and in new molecular targets related to ALS pathogenesis and disease progression. Additionally, new insights into the involvement of altered transcriptional profiles of noncoding RNAs (microRNA and lncRNA) and ALS-associated ribosomal binding proteins have been investigated, to understand the functional consequences of extensive RNA dysregulation in ALS. Attention has been also turned on how transcriptome alterations could highlight new molecular targets for drug development.

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Nuclear RNA foci from C9ORF72 expansion mutation form paraspeckle-like bodies

Cited by 42 publications

References 66 publications

G-quadruplexes offer a conserved structural motif for NONO recruitment to NEAT1 architectural lncRNA

G-quadruplexes offer a conserved structural motif for NONO recruitment to NEAT1 architectural lncRNA

Role of Site-Specific Glycosylation in the I-Like Domain of Integrin β1 in Small Extracellular Vesicle-Mediated Malignant Behavior and FAK Activation

RNA Metabolism and Therapeutics in Amyotrophic Lateral Sclerosis

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