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A Benzophenone-Based Photocaging Strategy for the N7 Position of Guanosine.

ABSTRACT: Selective modification of nucleobases with photolabile caging groups enables the study and control of processes and interactions of nucleic acids. Numerous positions on nucleobases have been targeted, but all involve formal substitution of a hydrogen atom with a photocaging group. Nature, however, also uses ring-nitrogen methylation, such as m⁷ G and m¹ A, to change the electronic structure and properties of RNA and control biomolecular interactions essential for translation and turnover. We report that aryl ketones such as benzophenone and α-hydroxyalkyl ketone are photolabile caging groups if installed at the N7 position of guanosine or the N1 position of adenosine. Common photocaging groups derived from the ortho-nitrobenzyl moiety were not suitable. Both chemical and enzymatic methods for site-specific modification of N7G in nucleosides, dinucleotides, and RNA were developed, thereby opening the door to studying the molecular interactions of m⁷ G and m¹ A with spatiotemporal control.

SUBMITTER: Anhauser L

PROVIDER: S-EPMC7012642 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A Benzophenone-Based Photocaging Strategy for the N7 Position of Guanosine.

Anhäuser Lea L Klöcker Nils N Muttach Fabian F Mäsing Florian F Špaček Petr P Studer Armido A Rentmeister Andrea A

Angewandte Chemie (International ed. in English) 20191230 8

Selective modification of nucleobases with photolabile caging groups enables the study and control of processes and interactions of nucleic acids. Numerous positions on nucleobases have been targeted, but all involve formal substitution of a hydrogen atom with a photocaging group. Nature, however, also uses ring-nitrogen methylation, such as m<sup>7</sup> G and m<sup>1</sup> A, to change the electronic structure and properties of RNA and control biomolecular interactions essential for translatio ...[more]

PMID: 31747109

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Project description:Hepatitis delta virus (HDV) is a significant human pathogen that causes acute and chronic liver disease; there is no licensed therapy. HDV is a circular negative-sense single-stranded RNA (ssRNA) virus that produces three RNAs in infected cells, genome, antigenome, and mRNA; the latter encodes hepatitis delta antigen (HDAg), the viral protein. These RNAs are synthesized by host DNA-dependent RNA polymerase acting as an RNA-dependent RNA polymerase. Although HDV genome RNA accumulates to high levels in infected cells, the mechanism by which this process occurs remains poorly understood. For example, the nature of the 5' end of the genome, including the synthesis start site and its chemical composition, is not known. Analysis of this process has been challenging because the initiation site is part of an unstable precursor in the rolling-circle mechanism by which HDV genome RNA is synthesized. In this study, circular HDV antigenome RNAs synthesized in vitro were used to directly initiate HDV genome RNA synthesis in transfected cells, thus enabling the detection of the 5' end of the genome RNA. The 5' end of this RNA is capped, as expected for a polymerase II product. Initiation begins at position 1646 on the genome, which is located near the loop end proximal to the start site for HDAg mRNA synthesis. Unexpectedly, synthesis begins with a guanosine that is not conventionally templated by the HDV RNA. IMPORTANCE Hepatitis delta virus (HDV) is a unique virus that causes severe liver disease. It uses host RNA polymerase II to copy its circular RNA genome in a unique and poorly understood process. Although the virus RNA accumulates to high levels within infected cells, it is not known how the synthesis of the viral RNA begins or even where on the genome synthesis starts. Here, we identify the start site for the initiation of HDV genome RNA synthesis as position 1646, which is at one end of the closed-hairpin-like structure of the viral RNA. The 5' end of the RNA is capped, as expected for polymerase II products. However, RNA synthesis begins with a guanosine that is not present in the genome. Thus, although HDV uses polymerase II to synthesize the viral genome, some details of the initiation process are different. These differences could be important for successfully targeting virus replication.

Project description:PurposeHepatocellular carcinoma (HCC) is a kind of primary liver cancer. It is a common malignant tumor of digestive system that is difficult to predict the prognosis of patients. As an important epigenetic modification, N7 methyl guanosine (m7G) is indispensable in gene regulation. This regulation may affect the development and occurrence of cancer. However, the prognosis of long non coding RNAs (lncRNAs) in HCC is limited, especially how m7G-related lncRNAs regulate the development of HCC has not been reported.MethodsThe Cancer Genome Atlas (TCGA) provides us with the expression data and corresponding clinical information of HCC patients we need. We used a series of statistical methods to screen four kinds of m7G-related lncRNAs related to HCC prognosis and through a series of verifications, the results were in line with our expectations. Finally, we also explored the IC50 difference and correlation analysis of various common chemotherapy drugs.ResultOur study identified four differentially expressed m7g-related lncRNAs associated with HCC prognosis. Survival curve analysis showed that high risk lncRNAs would lead to poor prognosis of HCC patients. M7G signature's AUC was 0.789, which shows that the prognosis model we studied has certain significance in predicting the prognosis of HCC patients. Moreover, our study found that different risk groups have different immune and tumor related pathways through gene set enrichment analysis. In addition, many immune cell functions are significantly different among different risk groups, such as T cell functions, including coordination of type I INF response and coordination of type II INF response. The expression of PDCD1, HHLA2, CTLA-4 and many other immune checkpoints in different risk groups is also different. Additionally, we analyzed the differences of IC50 and risk correlation of 15 chemotherapeutic drugs among different risk groups.ConclusionA novel lncRNAs associated with m7G predicts the prognosis of HCC.

Dataset Information

A Benzophenone-Based Photocaging Strategy for the N7 Position of Guanosine.

Publications

A Benzophenone-Based Photocaging Strategy for the N7 Position of Guanosine.

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