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      The Telomeric Response to Viral Infection

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          Abstract

          The ends of linear genomes, whether viral or cellular, can elicit potent DNA damage and innate immune signals. DNA viruses entering the nucleus share many features with telomeres in their ability to either suppress or co-opt these pathways. Here, we review some of the common mechanisms that viruses and telomeres use to manage the DNA damage and innate immune response pathways. We highlight recent studies on the role of the telomere repeat-containing RNA (TERRA) in response to viral infection. We discuss how TERRA can be activated through a p53-response element embedded in a retrotransposon-like repeat found in human subtelomeres. We consider how TERRA can function as a danger signal when secreted in extracellular vesicles to induce inflammatory cytokines in neighboring cells. These findings suggest that TERRA may be part of the innate immune response to viral infection, and support the hypothesis that telomeres and viruses utilize common mechanisms to maintain genome integrity and regulate innate immunity.

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          Most cited references 93

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          Alternative lengthening of telomeres: models, mechanisms and implications.

          Unlimited cellular proliferation depends on counteracting the telomere attrition that accompanies DNA replication. In human cancers this usually occurs through upregulation of telomerase activity, but in 10-15% of cancers - including some with particularly poor outcome - it is achieved through a mechanism known as alternative lengthening of telomeres (ALT). ALT, which is dependent on homologous recombination, is therefore an important target for cancer therapy. Although dissection of the mechanism or mechanisms of ALT has been challenging, recent advances have led to the identification of several genes that are required for ALT and the elucidation of the biological significance of some phenotypic markers of ALT. This has enabled development of a rapid assay of ALT activity levels and the construction of molecular models of ALT.
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            IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection.

            Inflammasomes are cytoplasmic sensors of foreign molecules, including pathogens, and function to induce caspase-1 activation and IL-1β cytokine maturation. Whether such a mechanism exists in the nucleus and is effective against nuclear replicating pathogens is unknown. Nuclear replicating herpesvirus KSHV is associated with Kaposi Sarcoma, an angioproliferative tumor characterized by an inflammatory microenvironment including IL-1β. We demonstrate that during KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome. This complex was initially detected in the nucleus and subsequently in the perinuclear area. KSHV gene expression and/or latent KSHV genome is required for inflammasome activation and IFI16 colocalizes with the KSHV genome in the infected cell nucleus. Caspase-1 activation by KSHV was reduced by IFI16 and ASC silencing. Our studies reveal IFI16 as a nuclear pathogen sensor and demonstrate that the inflammasome also functions in the nucleus. Copyright © 2011 Elsevier Inc. All rights reserved.
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              TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres.

              Telomere-repeat-encoding RNA (referred to as TERRA) has been identified as a potential component of yeast and mammalian telomeres. We show here that TERRA RNA interacts with several telomere-associated proteins, including telomere repeat factors 1 (TRF1) and 2 (TRF2), subunits of the origin recognition complex (ORC), heterochromatin protein 1 (HP1), histone H3 trimethyl K9 (H3 K9me3), and members of the DNA-damage-sensing pathway. siRNA depletion of TERRA caused an increase in telomere dysfunction-induced foci, aberrations in metaphase telomeres, and a loss of histone H3 K9me3 and ORC at telomere repeat DNA. Previous studies found that TRF2 amino-terminal GAR domain recruited ORC to telomeres. We now show that TERRA RNA can interact directly with the TRF2 GAR and ORC1 to form a stable ternary complex. We conclude that TERRA facilitates TRF2 interaction with ORC and plays a central role in telomere structural maintenance and heterochromatin formation.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                09 August 2017
                August 2017
                : 9
                : 8
                Affiliations
                The Wistar Institute, Philadelphia, PA 19104, USA; zwang@ 123456wistar.org (Z.W.); dengz@ 123456wistar.org (Z.D.); stutton@ 123456wistar.org (S.T.)
                Author notes
                [* ]Correspondence: lieberman@ 123456wistar.org ; Tel.: +1-215-898-9491
                Article
                viruses-09-00218
                10.3390/v9080218
                5580475
                28792463
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Review

                Microbiology & Virology

                innate immunity, exosomes, p53, ifi16, nd10, pml-nb, virus, telomere, alt, terra

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