Role of 2-5A-dependent RNase-L in senescence and longevity

Andersen, Jesper B.; Li, X. L.; Judge, Carianne S.; Zhou, Aimin; Jha, Babal K.; Shelby, Shameka J.; Zhou, Longhu; Silverman, Robert H.; Hassel, Bret A.

doi:10.1038/sj.onc.1210111

Cited by 42 publications

(46 citation statements)

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“…A number of IFN response genes have been linked to growth inhibition, senescence and apoptosis [49][50][51][52]. Our results suggest that under normal conditions, IFN-related genes are mostly repressed by the BRCA2 complex, and this repression is released in BRCA2 knockout cells.…”

Section: Discussionmentioning

confidence: 48%

Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

Jian

Viré

et al. 2014

J. Pathol.

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BRCA2 mutations are significantly associated with early onset breast cancer, and the tumour suppressing function of BRCA2 has been attributed to its involvement in homologous recombination [1]-mediated DNA repair. In order to identify additional functions of BRCA2, we generated BRCA2-knockout HCT116 human colorectal carcinoma cells. Using genome-wide microarray analyses, we have discovered a link between the loss of BRCA2 and the up-regulation of a subset of interferon (IFN)-related genes, including APOBEC3F and APOBEC3G. The overexpression of IFN-related genes was confirmed in different human BRCA2 −/− and mouse Brca2 −/− tumour cell lines, and was independent of either senescence or apoptosis. In isogenic wild type BRCA2 cells, we observed over-expression of IFN-related genes after treatment with DNAdamaging agents, and following ionizing radiation. Cells with endogenous DNA damage because of defective BRCA1 or RAD51 also exhibited over-expression of IFN-related genes. Transcriptional activity of the IFN-stimulated response element (ISRE) was increased in BRCA2 The GEO number for microarray analysis is GSE54830. Author contributionsHX designed the study, carried out most experiments and wrote the manuscript. JX made the BRCA2 knockout cell lines in HCT116, performed DNA damage repair experiments on BRCA2 knockout cells and wrote part of the manuscript. EV performed the CHIP experiment and was involved in manuscript writing. SJ analyzed the data. JW carried out microarray analysis. RT and VW carried out experiments. TK, CC and SA were involved in study design.

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Section: Discussionmentioning

confidence: 48%

Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

Jian

Viré

et al. 2014

J. Pathol.

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“…The TD and Rnasel −/− mice are currently in widespread many different labs investigating antiviral innate immunity. In addition, Bret Hassel's group reported with us that the Rnasel −/− mice have extended lifespans and that RNase L has a role in cell senescence [77]. Therefore, the Rnasel −/− mice may be useful in aging research.…”

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

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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“…A global comparison of transcripts and proteins bound to both RNase L and TTP will provide a more complete picture of the factors that mediate RNase L substrate targeting in the context of mitogen stimulation. RNase L mediates diverse antiproliferative activities, including quiescence (11), senescence (24), and apoptosis (25,26). Our results demonstrated that RNase L down-regulates mitogen-induced gene expression via transcriptional and post-transcriptional mechanisms suggesting that it plays a functional role to attenuate the proliferative response.…”

Section: Discussionmentioning

confidence: 71%

“…6). Both RNase L and TTP mediate antiproliferative and tumor suppressor activities (6,7,20,(23)(24)(25)(26)64); accordingly, genetic disruption or inactivating mutations in either protein lead to a transformed phenotype in vitro and tumorigenesis in vivo (27,28,101). Furthermore, mutations in RNase L and TTP are correlated with poor prognosis in several human cancers (6, 29 -32, 102).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, understanding the mechanisms by which this response is regulated is essential to identify therapeutic targets for neoplastic disorders. RNase L functions as an endogenous proliferative constraint (23)(24)(25)(26), and TTP is induced by mitogenic stimulation as a feedback mechanism to attenuate the proliferative response (76,90). In light of recent findings demonstrating the regulation of TTP mRNA by RNase L (23), and the interaction of RNase L and TTP proteins (45), we sought to investigate the RNase L-mediated regulation of TTP following mitogen stimulation that is relevant to their roles as antiproliferative effectors and to their mechanisms of action in the post-transcriptional control of target mRNA turnover.…”

Section: Discussionmentioning

confidence: 99%

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RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

Brennan-Laun

Ezelle

et al. 2014

Journal of Biological Chemistry

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Background: Serum-response factor (SRF) induces mRNAs that promote cell proliferation, whereas RNase L and tristetraprolin (TTP) degrade specific mRNAs to inhibit proliferation. Results: RNase L and TTP interact and down-regulate SRF to attenuate mitogen-induced gene expression. Conclusion: RNase L and TTP are components of a regulatory network that limits the proliferative response to mitogens. Significance: The RNase L/TTP axis represents a target to inhibit cancer cell proliferation.

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Role of 2-5A-dependent RNase-L in senescence and longevity

Cited by 42 publications

References 39 publications

Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

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

RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

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