Structural characterization of NORAD reveals a stabilizing role of spacers and two new repeat units

Chorostecki, Uciel; Saus, Ester; Gabaldón, Toni

doi:10.1016/j.csbj.2021.05.045

Cited by 10 publications

(26 citation statements)

References 54 publications

(78 reference statements)

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“…We found that A‐to‐I editing is linked to the alteration of interactions with phase‐separating proteins. In general, our predictions of A‐to‐I modifications effects on RNA structure reproduce experimental data to a remarkable extent, not only on the training set but also on an independent set 12 . Yet, we cannot exclude that changes in RNA structure could be attributable to interactions that are nonphysically related to ADAR.…”

Section: Discussionmentioning

confidence: 50%

“…These condensates are generated through the formation of multivalent interactions between NORAD and PUMILIO and also among PUMILIO proteins themselves 6 . NORAD contains 12 repeat units (of approximately 300 nt) where the sequence pattern UGURUAUA is repeated 12,57 . Recently, it has been shown that NORAD can be methylated at adenosine residues and this would decrease the number of PUMILIO proteins sequestered, 58 indicating that RNA modifications can modulate lncRNA activity.…”

Section: Resultsmentioning

confidence: 99%

“…Using CROSSalive, we reproduced the secondary structure content, as probed by nextPARS experiments, 12 to a remarkable extent, obtaining an AUC of 0.76 for the ADAR+ model and an AUC of 0.77 for the ADAR− model (Image S2; Experimental Procedures). As the nextPARS experiments were carried out in vitro, 8 and CROSSalive computes the structural content in the presence or absence of ADAR, the goodness of our performances indicates that NORAD structure does not change significantly in the two different experimental setups.…”

Section: Resultsmentioning

confidence: 99%

“…Both methods achieved an AUC of 0.85 (Figure S2). Finally, we employed nextPARS 12 experiments on NORAD (Supporting Information) and measured the performances of both ADAR+/− ANNs on the top/bottom 10% nucleotides ranked on nextPARS score, achieving an AUC of 0.77 (Figure S1). No significant difference exists between PARS and nextPARS protocols, except that nextPARS has higher throughput and sample multiplexing in comparison to PARS 48 …”

Section: Methodsmentioning

confidence: 99%

“…In order to do so, NORAD can sequester and inhibit Pumilio (PUM) proteins by promoting the formation of phase‐separated PUM condensates called NP bodies. Disruption of these condensates leads to genomic instability due to PUM hyperactivity 11,12 . Similarly, the architectural lncRNA NEAT1, has modular domains specifically arranged to bind NONO proteins and form paraspeckle compartments 13 .…”

Section: Introductionmentioning

confidence: 99%

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A high‐throughput approach to predict A‐to‐I effects on RNA structure indicates a change of double‐stranded content in noncoding RNAs

et al. 2022

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RNA molecules undergo a number of chemical modifications whose effects can alter their structure and molecular interactions. Previous studies have shown that RNA editing can impact the formation of ribonucleoprotein complexes and influence the assembly of membrane‐less organelles such as stress granules. For instance, N6‐methyladenosine (m6A) enhances SG formation and N1‐methyladenosine (m1A) prevents their transition to solid‐like aggregates. Yet, very little is known about adenosine to inosine (A‐to‐I) modification that is very abundant in human cells and not only impacts mRNAs but also noncoding RNAs. Here, we introduce the CROSSalive predictor of A‐to‐I effects on RNA structure based on high‐throughput in‐cell experiments. Our method shows an accuracy of 90% in predicting the single and double‐stranded content of transcripts and identifies a general enrichment of double‐stranded regions caused by A‐to‐I in long intergenic noncoding RNAs (lincRNAs). For the individual cases of NEAT1, NORAD, and XIST, we investigated the relationship between A‐to‐I editing and interactions with RNA‐binding proteins using available CLIP data and catRAPID predictions. We found that A‐to‐I editing is linked to the alteration of interaction sites with proteins involved in phase separation, which suggests that RNP assembly can be influenced by A‐to‐I. CROSSalive is available at http://service.tartaglialab.com/new_submission/crossalive.

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Section: Discussionmentioning

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A high‐throughput approach to predict A‐to‐I effects on RNA structure indicates a change of double‐stranded content in noncoding RNAs

et al. 2022

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A hybrid approach to assess the structural impact of long noncoding RNA mutations uncovers key NEAT1 interactions in colorectal cancer

et al. 2023

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Long noncoding RNAs (lncRNAs) are emerging players in cancer and they entail potential as prognostic biomarkers or therapeutic targets. Earlier studies have identified somatic mutations in lncRNAs that are associated with tumor relapse after therapy, but the underlying mechanisms behind these associations remain unknown. Given the relevance of secondary structure for the function of some lncRNAs, some of these mutations may have a functional impact through structural disturbance. Here, we examined the potential structural and functional impact of a novel A > G point mutation in NEAT1 that has been recurrently observed in tumors of colorectal cancer patients experiencing relapse after treatment. Here, we used the nextPARS structural probing approach to provide first empirical evidence that this mutation alters NEAT1 structure. We further evaluated the potential effects of this structural alteration using computational tools and found that this mutation likely alters the binding propensities of several NEAT1‐interacting miRNAs. Differential expression analysis on these miRNA networks shows upregulation of Vimentin, consistent with previous findings. We propose a hybrid pipeline that can be used to explore the potential functional effects of lncRNA somatic mutations.

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Expression of NORAD correlates with breast cancer aggressiveness and protects breast cancer cells from chemotherapy

Alves-Vale,

Capela,

Tavares-Marcos

et al. 2023

Molecular Therapy - Nucleic Acids

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Structural characterization of NORAD reveals a stabilizing role of spacers and two new repeat units

Abstract: Graphical abstract

Cited by 10 publications

References 54 publications

A high‐throughput approach to predict A‐to‐I effects on RNA structure indicates a change of double‐stranded content in noncoding RNAs

A high‐throughput approach to predict A‐to‐I effects on RNA structure indicates a change of double‐stranded content in noncoding RNAs

A hybrid approach to assess the structural impact of long noncoding RNA mutations uncovers key NEAT1 interactions in colorectal cancer

Expression of NORAD correlates with breast cancer aggressiveness and protects breast cancer cells from chemotherapy

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