Context-specific effects of sequence elements on subcellular localization of linear and circular RNAs

Ron, Maya; Ulitsky, Igor

doi:10.1038/s41467-022-30183-0

Cited by 21 publications

(20 citation statements)

References 86 publications

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“…Hosts including humans rely upon an intricate balance of m 6 A modifications to safeguard genome integrity. Thousands of m 6 A-marked intronic L1s (MILs) discovered in a variety of fetal tissues can block the transcription of long genes and impede host gene expression resulting in disease; conversely, the host uses effective countermeasures including the nuclear matrix RNA binding-protein SAFB [774]-a novel m 6 A reader complex-to bind and reduce MILs and protect host gene transcription processes [775]. In general, m 6 A positively regulates the expression of autonomous L1s and facilitates L1 retrotransposition by promoting the docking of eukaryotic initiation factor 3 (eIF3) on L1 5′ UTR to generate retrotransposition-competent L1 RNPs, whereas the m 6 A "eraser" ALKBH5 suppresses retrotransposition [776].…”

Section: A Modifications Regulate Sars-cov-2-mediated Line1 Derepressionmentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

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Section: A Modifications Regulate Sars-cov-2-mediated Line1 Derepressionmentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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“…In summary, our study provides new insights into the possible regulatory roles of SAFB. In addition to roles in the establishment and maintenance of heterochromatin (Huo et al 2020; McCarthy et al 2021), the nuclear retention of RNA (Ron and Ulitsky 2022), and the response to stress (Aly et al 2019), our work suggests that SAFB may boost the overall expression of certain genes by associating with GA-rich regions in nascent RNA.…”

Section: Discussionmentioning

confidence: 87%

“…SAFB has also been implicated in regulating the response to heat shock in human cells, where along with other RNA-binding proteins, it becomes enriched in nuclear condensates centered around specific satellite RNAs (Aly et al 2019). Additionally, SAFB plays a role in the nuclear retention of unspliced RNAs (Ron and Ulitsky 2022), and has been shown to be important for the maintenance of heterochromatin in mouse and human cells, possibly through its ability to associate with specific RNAs (Huo et al 2020; McCarthy et al 2021).…”

Section: Introductionmentioning

confidence: 99%

SAFB associates with nascent RNAs to promote gene expression in mouse embryonic stem cells

Cherney

Eberhard

Mills

et al. 2022

Preprint

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Scaffold Attachment Factor B (SAFB) is a conserved RNA Binding Protein (RBP) that is essential for early mammalian development. However, the RNAs that associate with SAFB in mouse embryonic stem cells have not been characterized. Here, we addressed this unknown using RNA-seq and SAFB RNA immunoprecipitation followed by RNA-seq (RIP-seq) in wild-type ESCs and in ESCs in which SAFB and SAFB2 were knocked out. SAFB predominantly associated with introns of protein-coding genes through purine-rich motifs. The transcript most enriched in SAFB association was the lncRNA Malat1, which also contains a purine-rich region in its 5' end. Knockout of SAFB/2 led to down- and upregulation of approximately 1,000 genes associated with multiple biological processes, including genes that are regulated by Polycomb and genes involved in apoptosis, cell division, and cell migration. The spliced and nascent transcripts of many downregulated genes associated with high levels of SAFB in wild-type cells, implying that SAFB binding promotes their expression. Reintroduction of SAFB into double-knockout cells restored gene expression towards wild-type levels, an effect that was again observable at the level of spliced and nascent transcripts. Proteomics analysis revealed a significant enrichment of nuclear speckle-associated and RS-domain containing proteins among SAFB interactors. Our findings suggest that among other potential functions in mouse embryonic stem cells, SAFB promotes the expression of a subset of genes through its ability to bind purine regions in nascent RNA.

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“…Interestingly, binding of SAFBs has very recently been brought in correlation with the nuclear localization of linear, mostly unspliced RNAs [74] indicating an anchoring role for them in transcript processing, which is susceptible to stress in a reversible manner [58].…”

Section: Discussionmentioning

confidence: 99%

Insight into the structural basis for dual nucleic acid - recognition by the Scaffold Attachment Factor B2 protein

Korn

Ehr

Dhamotharan

et al. 2022

Preprint

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The family of scaffold attachment factor B (SAFB) proteins comprises three members and was first identified as binders of the nuclear matrix/scaffold. Over the past two decades, SAFBs were shown to act in DNA repair, mRNA/(l)ncRNA processing, and as part of protein complexes with chromatin-modifying enzymes. SAFB proteins are approximately-100-kDa-sized dual nucleic acid-binding proteins with dedicated domains in an otherwise largely unstructured context, but whether and how they discriminate DNA- and RNA-binding has remained enigmatic. We here provide the SAFB2 DNA- and RNA-binding SAP and RRM domains in their functional boundaries and use solution NMR spectroscopy to ascribe DNA- and RNA-binding functions. We give insight into their target nucleic acid preferences and map the interfaces with respective nucleic acids on sparse data-derived SAP and RRM domain structures. Further, we provide evidence that the SAP domain exhibits intra-domain dynamics and a potential tendency to dimerise, which may expand its specifically targeted DNA sequence range. Our data provide a first molecular basis of and a starting point towards deciphering DNA- and RNA-binding functions of SAFB2 on the molecular level and serve a basis for understanding its localization to specific regions of chromatin and its involvement in the processing of specific RNA species.

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Context-specific effects of sequence elements on subcellular localization of linear and circular RNAs

Cited by 21 publications

References 86 publications

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

SAFB associates with nascent RNAs to promote gene expression in mouse embryonic stem cells

Insight into the structural basis for dual nucleic acid - recognition by the Scaffold Attachment Factor B2 protein

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