Interferon, double-stranded RNA and RNA degradation. Fractionation of the endonucleaseINT system into two macromolecular components; Role of a small molecule in nuclease activation

Ratner, Lee; Wiegand, Roger C.; Farrell, Paul J.; Sen, Ganes C.; Cabrer, Bartolomé; Lengyel, Péter

doi:10.1016/0006-291x(78)91443-2

Cited by 131 publications

(51 citation statements)

References 12 publications

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“…By that time, members of the Kerr lab (notably Ara Hovanessian and Bryan Williams with collaborator Michael Clemens) had firmly laid the groundwork by discovering 2-5A synthetase (OAS) activity [32], elucidating the chemical structure of 2-5A [9], and demonstrating that isolated and purified 2-5A activated the 2-5A dependent RNase [33](now referred to as "RNase L"; the "L" stands for "latent"). Complementary work in the labs of Peter Lengyel, Michel Revel, Corrado Baglioni and Charles Samuel gave impetus to these early studies [34][35][36][37]. I came to the Kerr lab because of my interest in unusual nucleotide regulators and my fascination with Ian Kerr's remarkable discovery of 2-5A [9,38].…”

Section: Monitoring the Presence And Activation Of Rnase L In Intact mentioning

confidence: 99%

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

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The antiviral and antitumor actions of interferons are caused, in part, by a remarkable regulated RNA cleavage pathway known as the 2-5A/RNase L system. 2′-5′ linked oligoadenylates (2-5A) are produced from ATP by interferon-inducible synthetases. 2-5A activates pre-existing RNase L, resulting in the cleavage of RNAs within single-stranded regions. Activation of RNase L by 2-5A leads to an antiviral response, although precisely how this happens is a subject of ongoing investigations. Recently, RNase L was identified as the hereditary prostate cancer 1 gene. That finding has led to the discovery of a novel human retrovirus, XMRV. My scientific journey through the 2-5A system recounts some of the highlights of these efforts. Knowledge gained from studies on the 2-5A system could have an impact on development of therapies for important viral pathogens and cancer.Keywords 2-5A; RNase L; interferon; cancer; virus Background on the 2-5A/RNase L systemOver the past thirty-years, investigations into the mechanisms of interferon (IFN) action have elucidated how antiviral innate immunity operates within and between mammalian cells. The focus of my work over this period has been, and continues to be, probing the biology and biochemistry of the 2-5A/RNase L system, and studying its roles in health and disease. My scientific journey, from basic research to clinical studies, are summarized in this monograph. The 2-5A/RNase L system is one the principal pathways by which IFNs suppress viral infections. Exposure of cells to IFNs induces expression of genes that result in an "antiviral state". Type I IFNs bind to the IFN-α receptor 1 (IFNAR1) and IFNAR2 polypeptide chains on cell surfaces initiating JAK-STAT signaling to the IFN stimulated genes (ISGs) [1]. Included among over a hundred different ISGs are genes encoding 2-5A synthetases (OAS) [2,3]. The OAS genes are a family of ISGs that function in the 2-5A/RNase L system (Fig. 1). In humans there are three functional OAS genes (OAS1-3), resulting in 8 to 10 OAS isoforms due to alternative mRNA splicing [4]. In mice, in addition to OAS2 and OAS3 there are 7 separate OAS1 genes, including OAS1b, the flavivirus resistance gene (Flv r ] [5][6][7][8]. When stimulated by dsRNA, the functional OAS proteins produce a series of short 5′-phosphorylated, 2′,5′-linked oligoadenylates collectively referred to as 2-5A [p x 5′A(2′p5′A) n ; x = 1-3; n≥2] from ATP [9]. The first molecular clone for an OAS was obtained by Michel Revel's lab [10]. Biochemical characterization of OAS proteins by Ara Hovanessian's lab [11][12][13][14] and Ganes Sen's lab [15][16][17][18][19] and a crystal structure by Rune Hartmann and Vivien Yee (in collaboration with Ganes Sen and Just Justesen) [20] have led to functional and structural insight into the OAS family of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, type...

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Section: Monitoring the Presence And Activation Of Rnase L In Intact mentioning

confidence: 99%

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

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“…These agents are needed for the activation of an endonuclease activity,* but do not have to be present during the cleavage of RNA (6,7). The "nuclease activators" that mediate the activation are 2'-5' linked oligoadenylates [(2'-5')An] with 5'-terminal triphosphate or diphosphate (8)(9)(10)(11)(12)(13)(14)(15)(16). This series of compounds was originally discovered as an inhibitor of protein synthesis that is formed from ATP in extracts of various interferon-treated cells (and in lysates from rabbit reticulocytes not treated with interferon) in the presence of double-stranded RNA (17)(18)(19)(20).…”

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“…This series of compounds was originally discovered as an inhibitor of protein synthesis that is formed from ATP in extracts of various interferon-treated cells (and in lysates from rabbit reticulocytes not treated with interferon) in the presence of double-stranded RNA (17)(18)(19)(20). The level of the enzyme catalyzing (2'-5')An synthesis is greatly increased in cells upon treatment with interferon (8,(21)(22)(23). The activation of the endonuclease by added (2'-5')An is transient in crude cell extracts.…”

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confidence: 99%

“…The enzyme was partially purified from mouse Ehrlich ascites tumor cells and L cells (8,11,12). In (25), the protein fraction tested for endonuclease activity (in [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ml), and the specified amount of (2'-5')An preparation I, II, or III if so indicated. After incubation at 30°C for 1 hr, the reaction was terminated and the reaction mixture was analyzed by polyacrylamide gel electrophoresis and radioautography.…”

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Interferon, double-stranded RNA, and RNA degradation: activation of an endonuclease by (2'-5')An.

Slattery¹,

Ghosh²,

Samanta³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

132

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“…Among the biochemical changes known to occur in IFN-treated cells is the induction of the enzymatic activity of (2'-5')oligoadenylate (2-5A) synthetase (5,15). This enzyme catalyzes the formation of ppp(A2'p)nA from ATP in the presence of double-stranded RNA, thus activating the 2-5A-dependent RNase L, which is normally present in the cell (3,14,20,27). It is generally accepted that RNase-L activity is responsible for the inhibition of protein synthesis by 2-5A, since it has been shown that this enzyme cleaves single-stranded RNA at UA or UU sites (28), thus degrading both mRNA and rRNA molecules (3,5).…”

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Isolation and characterization of an interferon-resistant cell line deficient in the induction of (2'-5')oligoadenylate synthetase activity.

Salzberg¹,

Wreschner²,

Oberman³

et al. 1983

Mol. Cell. Biol.

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To screen for cells with different sensitivities to interferon (IFN), NIH 3T3 mouse fibroblasts were subcloned and examined for their response to IFN treatment. Of 30 clones tested, 2 appeared to be relatively resistant to IFN, since the replication of both vesicular stomatitis virus and mengovirus was not inhibited, even in the presence of 1,000 U of IFN per ml. One resistant (A10) and one sensitive (A5) clone were further analyzed. In both clones, murine leukemia virus replication was equally inhibited by IFN, indicating the presence of functional receptors for IFN in the resistant clone. Using the (2'-5')oligoadenylate (2-5A) radiobinding assay, we could demonstrate that both clones contained the RNase L protein. Furthermore, this enzyme appears to be active, since a similar reduction in the rate of protein synthesis was evident after the introduction of exogenous 2-5A to the cells. We also analyzed the activity of another enzyme in the 2-5A pathway, namely, 2-5A synthetase. In the sensitive cells (AS), the induction of enzyme activity was proportional to the IFN concentration used, reaching a maximum of more than a 10-fold increase over the background of untreated cells. However, little if any induction over the basal activity was observed in the resistant cells (A10) when similar doses of IFN were used. It is thus probable that the lack of induction of 2-5A synthetase activity by IFN in A10 cells is at least partly responsible for their relative resistance to IFN treatment.

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Interferon, double-stranded RNA and RNA degradation. Fractionation of the endonucleaseINT system into two macromolecular components; Role of a small molecule in nuclease activation

Cited by 131 publications

References 12 publications

A scientific journey through the 2-5A/RNase L system

A scientific journey through the 2-5A/RNase L system

Interferon, double-stranded RNA, and RNA degradation: activation of an endonuclease by (2'-5')An.

Isolation and characterization of an interferon-resistant cell line deficient in the induction of (2'-5')oligoadenylate synthetase activity.

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