Epitranscriptomic marks: Emerging modulators of RNA virus gene expression

Netzband, Rachel; Pager, Cara T.

doi:10.1002/wrna.1576

Cited by 59 publications

(72 citation statements)

References 195 publications

(361 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Both SARS-CoV-1 and -2 have a single-stranded RNA with ~ 30,000 nucleotides with 5′-cap structure and 3′-poly-A tail ( Figure 1A) [1][2][3]. Many RNA viruses, including CoVs, replicate in the cytoplasm using their own viral 2′-O MTases, such as nsp16, which catalyze the formation of cap structures on viral mRNA that mimic those present on host mRNAs [59,60]. Previous studies on SARS-CoV-1 and MERS-CoV demonstrated that targeting nsp16 has the potential to interfere with viral replication both at the level of inhibition of the replication process and in promoting intracellular recognition and immune response to viral RNA species [8][9][10] [27][28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Jiang¹,

Liu²,

Manning³

et al. 2020

Preprint

View full text Add to dashboard Cite

Three coronaviruses (CoVs): severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and the recently identified SARS-CoV-2 in December 2019, have caused deadly pneumonia in humans since the beginning of the 21st century. The SARS-CoV-2 causes coronavirus disease-19 (COVID-19) with influenza-like symptoms ranging from mild discomfort to severe lung injury and multi-organ failure, eventually leading to death. As of April 30, 2020, more than three million (3,175,207) COVID-19 cases were reported worldwide, and more than 220,000 (224,172) patients have died (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Thus, it will be of great benefit to identify and repurpose already well-characterized compounds and approved drugs for use in combating COVID-19. CoVs are positive-sense RNA viruses that replicate in the cytoplasm of infected cells. Replication and transcription of the CoV RNA genome are achieved by a complex RNA replication/transcription machinery, consisting of at least 16 viral nonstructural proteins (nsp). Previous studies demonstrated that nsp16 proteins of SARS-CoV-1 and MERS-CoV have methyltransferase (MTase) activities that catalyze methylation of the first transcribed nucleotide at the ribose 2’-O position (2’-O-Me). The 2’-O-Me of virus cap RNAs protects itself from degradation by 5′-3′ exoribonucleases, ensures efficient translation, and helps to prevent recognition by the host innate immune system. The importance of nsp16 2'-O-MTase activity for CoV infection and pathogenesis was previously documented by in vitro and in vivo studies. For SARS-CoV-1, the absence of nsp16 2′-O-MTase activity results in significant attenuation characterized by decreased viral replication, reduced weight loss, and limited breathing dysfunction in mice. In addition, nsp16 down-regulates the activities of innate immune sensing factors: retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 protein (MDA5). Thus, inhibition of nsp16 2’-O-MTase activities should restrain viral replication and enable recognition by the host innate immune system, making the nsp16-MTase a promising target for the identification of new anti-SARS-CoV-2 drugs. In the present study, we employed structural analysis, virtual screening, and systematic drug repurposing approaches to identify “approved” drugs which can act as promising inhibitors against nsp16 2′-O-MTase of SARS-CoV-2. We first performed comparative analysis of primary amino acid sequences and crystal structures of seven human CoVs and defined the key residues for nsp16 2-O’-MTase functions. From the virtual screening against nsp16 2′-O-MTase of SARS-CoV-2, we provide a ranking of the predicted binding affinities of 1,380 top hit compounds corresponding to 967 “approved” drugs. Furthermore, we have calculated various structural parameters of our top-ranking drugs. Our studies provided the foundation to further test and repurpose these candidate drugs experimentally and clinically for COVID-19 treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Jiang¹,

Liu²,

Manning³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In recent years, with the advent and development of high-throughput sequencing technologies coupled with direct RNA-sequencing technologies, the focus has shifted to the study of epigenetic modifications of RNA (3,4). Based on these sequencing technologies, published data reveals that RNA contains multiple dynamic modifications, among which the most studied are N6-methyladenosine (m 6 A), 5-methylcytosine (m 5 C), N1methyladenosine (m 1 A), N7-methylguanosine(N 7 G), and ribose 2 ′ -O-methylation, as well as pseudouridine (Ψ ) and inosine (I) (5)(6)(7)(8)(9). The dynamic regulation and disorder of these RNA modifications are also significantly related to the occurrence, maintenance and progression of tumors (10,11).…”

Section: Introductionmentioning

confidence: 99%

Identification of RNA: 5-Methylcytosine Methyltransferases-Related Signature for Predicting Prognosis in Glioma

Wang

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

Background: Glioma is the most common primary intracranial tumor, accounting for the vast majority of intracranial malignant tumors. Aberrant expression of RNA:5-methylcytosine(m 5 C) methyltransferases have recently been the focus of research relating to the occurrence and progression of tumors. However, the prognostic value of RNA:m 5 C methyltransferases in glioma remains unclear. This study investigated RNA: m 5 C methyltransferase expression and defined its clinicopathological signature and prognostic value in gliomas. Methods: We obtained the RNA-sequence and Clinicopathological data of RNA:m 5 C methyltransferases underlying gliomas from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets. We analyzed the expression of RNA:m 5 C methyltransferase genes in gliomas with different clinicopathological characteristics and identified different subtypes using Consensus clustering analysis. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) was used to annotate the function of these genes. Univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm analyses were performed to construct the risk signature. Kaplan-Meier method and Receiver operating characteristic (ROC) curves were used to assess the overall survival of glioma patients. Additionally, Cox proportional regression model analysis was developed to address the connections between the risk scores and clinical factors. Results: We revealed the differential expression of RNA:m 5 C methyltransferase genes in gliomas with different clinicopathological features. Consensus clustering of RNA:m 5 C methyltransferases identified three clusters of gliomas with different prognostic and clinicopathological features. Meanwhile, functional annotations demonstrated that RNA:m 5 C methyltransferases were significantly associated with the malignant progression of gliomas. Thereafter, five RNA:m 5 C methyltransferase genes were screened to construct a risk signature that can be used to predict not only overall survival Wang et al. RNA:m 5 C Methyltransferases in Glioma but also clinicopathological features in gliomas. ROC curves revealed the significant prognostic ability of this signature. In addition, Multivariate Cox regression analyses indicated that the risk score was an independent prognostic factor for glioma outcome. Conclusion: We demonstrated the prognostic role of RNA:m 5 C methyltransferases in the initiation and progression of glioma. We have expanded on the understanding of the molecular mechanism involved, and provided a unique approach to predictive biomarkers and targeted therapy for gliomas.

show abstract

“…Viral epitranscriptomics is an emerging field, which refers to post-transcriptional modifications of RNA and plays an important role in the life cycles of different viruses including human coronavirus 3 . 2′-O-methylation (2′OMe) is one of the most common modification in the viral RNA including SARS-CoV-2 RNA 1 , 2 .…”

mentioning

confidence: 99%

RNA 2′-O-methylation modification and its implication in COVID-19 immunity

Paramasivam

2020

Cell Death Discov.

View full text Add to dashboard Cite

Epitranscriptomic marks: Emerging modulators of RNA virus gene expression

Cited by 59 publications

References 195 publications

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Identification of RNA: 5-Methylcytosine Methyltransferases-Related Signature for Predicting Prognosis in Glioma

RNA 2′-O-methylation modification and its implication in COVID-19 immunity

Contact Info

Product

Resources

About