The NORAD lncRNA assembles a topoisomerase complex critical for genome stability

Munschauer, Mathias; Nguyen, Celina T.; Sirokman, Klara; Hartigan, Christina R.; Hogstrom, Larson; Engreitz, Jesse M.; Ulirsch, Jacob C.; Fulco, Charles P.; Subramanian, Vidya; Chen, Jenny; Schenone, Monica; Guttman, Mitchell; Carr, Steven A.; Lander, Eric S.

doi:10.1038/s41586-018-0453-z

Cited by 305 publications

(313 citation statements)

References 55 publications

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“…11 Long non coding RNA (LncRNA) is a series of non coding RNA that is longer than 200 nt and is not coding protein. 12 LncRNA has been well-studied in different diseases, including cerebral stroke, 13 heart development, 14 and tumor development. 15 For example, lncRNA ROCR suppressed endogenous cardiac regeneration by targeting the PTEN/Akt pathway.…”

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confidence: 99%

Overexpression of lncRNA Gm2691 attenuates apoptosis and inflammatory response after myocardial infarction through PI3K/Akt signaling pathway

Tian

et al. 2019

IUBMB Life

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Acute myocardial infarction is one of the most threatening disease in the world. In previous studies, numerous dysregulated lncRNAs exposed to ischemic reperfusion injury have been identified. In this differential lncRNAs, Gm2691 attracted our attention due to its high fold change. The aim of the study was to investigate the function and mechanism of lncRNA Gm2691 in ischemic reperfusion injury. AnaeroPack anaerobic system treated neonatal rat ventricular cardiomyocytes were used to analyze the function of lncRNA Gm2691 in vitro. Tunel, Caspase3, and inflammation markers were detected to evaluate apoptosis and inflammatory response. Rat acute myocardial infarction was performed to elucidate the function of lncRNA Gm2691 in vivo. The results showed that LncRNA Gm2691 improved the cardiac function and attenuated the inflammatory response in vivo. We also found that lncRNA Gm2691 reduced the apoptosis and improved cell survival rates in anaeroPack anaerobic system treated neonatal rat ventricular cardiomyocytes. Western blot analysis revealed that lncRNA Gm2691 decreased Akt and ERK1/2 activities, suggesting that lncRNA Gm2691 may functioned through Akt signaling pathway. We verified the function and mechanism of lncRNA Gm2691 and provide evidence that lncRNA Gm2691 may play important role in ischemic reperfusion injury, and understanding the precise role of Gm2691 will undoubtedly shed new light on the clinical treatment.

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confidence: 99%

Overexpression of lncRNA Gm2691 attenuates apoptosis and inflammatory response after myocardial infarction through PI3K/Akt signaling pathway

Tian

et al. 2019

IUBMB Life

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“…Many studies have suggested that noncoding RNAs participate in the formation of protein complexes (McHugh et al, 2015;Munschauer et al, 2018;Wen et al, 2018). Previous results have suggested that Rad17 interacts with RFC2-5 (Majka and Burgers, 2004).…”

Section: Discussionmentioning

confidence: 99%

The noncoding function of NELFA mRNA promotes the development of oesophageal squamous cell carcinoma by regulating the Rad17‐RFC2‐5 complex

Wang

Gong

et al. 2020

Molecular Oncology

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Recently, RNAs interacting with proteins have been implicated in playing an important role in the occurrence and progression of oesophageal squamous cell carcinoma (ESCC). In this study, we found that NELFA mRNA interacts with Rad17 through a novel noncoding mode in the nucleus and that the aberrant expression of USF2 contributed to the upregulation of Rad17 and NELFA. Subsequent experiments demonstrated that the deletion of NELFA mRNA significantly decreased ESCC proliferation and colony formation in vitro. Moreover, NELFA mRNA knockdown inhibited DNA damage repair and promoted apoptosis. Mechanistic studies indicated that NELFA mRNA regulated the interaction between Rad17 and RFC2‐5, which had a major impact on the phosphorylation of CHK1, CHK2 and BRCA1. NELFA mRNA expression was consistently elevated in ESCC patients and closely related to decreased overall survival. Taken together, our results confirmed the critical role of the noncoding function of NELFA mRNA in ESCC tumorigenesis and indicated that NELFA mRNA can be regarded as a therapeutic target and an independent prognostic indicator in ESCC patients.

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“…An alternative (but not excluding) mechanism to explain the relationship between NORAD and genomic stability was recently proposed by Munschauer et al . They showed that, after subjecting cells to replication stress or DNA damage, a new nuclear ribonucleoprotein complex, named NARC1 (NORAD‐activated ribonucleoprotein complex 1), is assembled by NORAD, recruiting proteins known to act as suppressors of genomic instability, such as topoisomerase I (TOP1), ALYREF and the PRPF19–CDC5L …”

Section: Lncrnas In Hallmarks Of Cancermentioning

confidence: 99%

“…139 An alternative (but not excluding) mechanism to explain the relationship between NORAD and genomic stability was recently proposed by Munschauer et al 140 They showed that, after subjecting cells to replication stress or DNA damage, a new nuclear ribonucleoprotein complex, named NARC1 (NORAD-activated ribonucleoprotein complex 1), is assembled by NORAD, recruiting proteins known to act as suppressors of genomic instability, such as topoisomerase I (TOP1), ALYREF and the PRPF19-CDC5L. 140 LncRNAs transcribed from α-satellite centromere region physically bind to the chaperone HJURP/CENP-A complex and facilitate the incorporation of CENP-A into centromeric chromatin. 141 In addition, α-satellite RNAs can also interact with the cohesin protector, SGO1, an essential effector for maintaining chromosome stability.…”

Section: Genomic Instabilitymentioning

confidence: 99%

Long non‐coding RNAs in cancer: Another layer of complexity

Oliveira

Mathias

et al. 2019

The Journal of Gene Medicine

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We review the most well characterized long non‐coding RNAs (lncRNAs) with important roles in hallmarks of cancer, additionally including lncRNAs with a higher potential for clinical application. LncRNAs are transcripts larger than 200 nucleotides in length that do not appear to have protein‐coding potential, although some of those may produce small functional peptides. These transcripts have attracted significant attention from researchers as a result of their role in genetic regulation, including epigenetic, transcriptional and post‐transcriptional regulation, being involved in numerous biological processes, as well as being associated with multifactorial diseases, including tumorigenesis. The hallmarks of cancer include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis and activating invasion/metastasis. Additionally, genome instability, inflammation, reprogramming of energy metabolism and evading immune destruction and lncRNAs are implicated in all hallmarks of cancer. Based on the great number of studies describing lncRNAs associated with diverse aspects of most tumor types, lncRNAs have essential roles in potentially all biological features of cancer cells and show great utility as diagnostic and prognostic markers, as exemplified by PCA3 lncRNA detection in prostate cancer diagnosis.

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The NORAD lncRNA assembles a topoisomerase complex critical for genome stability

Cited by 305 publications

References 55 publications

Overexpression of lncRNA Gm2691 attenuates apoptosis and inflammatory response after myocardial infarction through PI3K/Akt signaling pathway

Overexpression of lncRNA Gm2691 attenuates apoptosis and inflammatory response after myocardial infarction through PI3K/Akt signaling pathway

The noncoding function of NELFA mRNA promotes the development of oesophageal squamous cell carcinoma by regulating the Rad17‐RFC2‐5 complex

Long non‐coding RNAs in cancer: Another layer of complexity

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