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  • 1
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    ATM, KAP1 and the Epstein–Barr virus polymerase processivity factor direct traffic at the intersection of transcription and replication
    Oxford University Press (OUP) ; 2023
    In:  Nucleic Acids Research Vol. 51, No. 20 ( 2023-11-10), p. 11104-11122
    Details
    In: Nucleic Acids Research, Oxford University Press (OUP), Vol. 51, No. 20 ( 2023-11-10), p. 11104-11122
    Abstract: The timing of transcription and replication must be carefully regulated for heavily-transcribed genomes of double-stranded DNA viruses: transcription of immediate early/early genes must decline as replication ramps up from the same genome—ensuring efficient and timely replication of viral genomes followed by their packaging by structural proteins. To understand how the prototypic DNA virus Epstein–Barr virus tackles the logistical challenge of switching from transcription to DNA replication, we examined the proteome at viral replication forks. Specifically, to transition from transcription, the viral DNA polymerase-processivity factor EA-D is SUMOylated by the epigenetic regulator and E3 SUMO-ligase KAP1/TRIM28. KAP1’s SUMO2-ligase function is triggered by phosphorylation via the PI3K-related kinase ATM and the RNA polymerase II-associated helicase RECQ5 at the transcription machinery. SUMO2-EA-D then recruits the histone loader CAF1 and the methyltransferase SETDB1 to silence the parental genome via H3K9 methylation, prioritizing replication. Thus, a key viral protein and host DNA repair, epigenetic and transcription-replication interference pathways orchestrate the handover from transcription-to-replication, a fundamental feature of DNA viruses.
    Type of Medium: Online Resource
    ISSN: 0305-1048 , 1362-4962
    URL: Article
    DOI: 10.1093/nar/gkad823
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 2
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    Beta human papillomavirus 8E6 promotes alternative end joining
    eLife Sciences Publications, Ltd ; 2023
    In:  eLife Vol. 12 ( 2023-01-24)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 12 ( 2023-01-24)
    Abstract: Double strand breaks (DSBs) are one of the most lethal DNA lesions in cells. The E6 protein of beta-human papillomavirus (HPV8 E6) impairs two critical DSB repair pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). However, HPV8 E6 only delays DSB repair. How DSBs are repaired in cells with HPV8 E6 remains to be studied. We hypothesize that HPV8 E6 promotes a less commonly used DSB repair pathway, alternative end joining (Alt-EJ). Using CAS9-based Alt-EJ reporters, we show that HPV8 E6 promotes Alt-EJ. Further, using small molecule inhibitors, CRISPR/CAS9 gene knockout, and HPV8 E6 mutant, we find that HPV8 E6 promotes Alt-EJ by binding p300, an acetyltransferase that facilitates DSB repair by HR and NHEJ. At least some of this repair occurs through a subset of Alt-EJ known as polymerase theta dependent end joining. Finally, whole genome sequencing analysis showed HPV8 E6 caused an increased frequency of deletions bearing the microhomology signatures of Alt-EJ. This study fills the knowledge gap of how DSB is repaired in cells with HPV8 E6 and the mutagenic consequences of HPV8 E6 mediated p300 destabilization. Broadly, this study supports the hypothesis that beta-HPV promotes cancer formation by increasing genomic instability.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.81923
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2023
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  • 3
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    Nascent Transcriptomics Reveal Cellular Prolytic Factors Upregulated Upstream of the Latent-to-Lytic Switch Protein of Epstein-Barr Virus
    American Society for Microbiology ; 2020
    In:  Journal of Virology Vol. 94, No. 7 ( 2020-03-17)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 94, No. 7 ( 2020-03-17)
    Abstract: Lytic activation from latency is a key transition point in the life cycle of herpesviruses. Epstein-Barr virus (EBV) is a human herpesvirus that can cause lymphomas, epithelial cancers, and other diseases, most of which require the lytic cycle. While the lytic cycle of EBV can be triggered by chemicals and immunologic ligands, the lytic cascade is activated only when expression of the EBV latent-to-lytic switch protein ZEBRA is turned on. ZEBRA then transcriptionally activates other EBV genes and, together with some of those gene products, ensures completion of the lytic cycle. However, not every latently infected cell exposed to a lytic trigger turns on the expression of ZEBRA, resulting in responsive and refractory subpopulations. What governs this dichotomy? By examining the nascent transcriptome following exposure to a lytic trigger, we find that several cellular genes are transcriptionally upregulated temporally upstream of ZEBRA. These genes regulate lytic susceptibility to various degrees in latently infected cells that respond to mechanistically distinct lytic triggers. While increased expression of these cellular genes defines a prolytic state, such upregulation also runs counter to the well-known mechanism of viral-nuclease-mediated host shutoff that is activated downstream of ZEBRA. Furthermore, a subset of upregulated cellular genes is transcriptionally repressed temporally downstream of ZEBRA, indicating an additional mode of virus-mediated host shutoff through transcriptional repression. Thus, increased transcription of a set of host genes contributes to a prolytic state that allows a subpopulation of cells to support the EBV lytic cycle. IMPORTANCE Transition from latency to the lytic phase is necessary for herpesvirus-mediated pathology as well as viral spread and persistence in the population at large. Yet, viral genomes in only some cells in a population of latently infected cells respond to lytic triggers, resulting in subpopulations of responsive/lytic and refractory cells. Our investigations into this partially permissive phenotype of the herpesvirus Epstein-Barr virus (EBV) indicate that upon exposure to lytic triggers, certain cellular genes are transcriptionally upregulated, while viral latency genes are downregulated ahead of expression of the viral latent-to-lytic switch protein. These cellular genes contribute to lytic susceptibility to various degrees. Apart from indicating that there may be a cellular “prolytic” state, our findings indicate that (i) early transcriptional upregulation of cellular genes counters the well-known viral-nuclease-mediated host shutoff and (ii) subsequent transcriptional downregulation of a subset of early upregulated cellular genes is a previously undescribed mode of host shutoff.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01966-19
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
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  • 4
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    Polymerase theta is a synthetic lethal target for killing Epstein-Barr virus lymphomas
    American Society for Microbiology ; 2024
    In:  Journal of Virology Vol. 98, No. 7 ( 2024-07-23)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 98, No. 7 ( 2024-07-23)
    Abstract: Epstein-Barr virus (EBV) contributes to ~2% of the global cancer burden. With a recent estimate of 〉 200,000 deaths a year, identifying molecular vulnerabilities will be key to the management of these frequently aggressive and treatment-resistant cancers. Building on our earlier work demonstrating reliance of EBV-cancers on microhomology-mediated end-joining repair, we now report that EBV lymphomas and transformed B cell lines abundantly express the MMEJ enzyme POLθ that likely protects cellular replication forks and repairs replication-related cellular DNA breaks. Importantly also, we show that a newly identified POLθ inhibitor kills EBV-cancer cells, revealing a novel strategy to block DNA replication and repair of these aggressive cancers.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.00572-24
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2024
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  • 5
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    IFI16 Partners with KAP1 to Maintain Epstein-Barr Virus Latency
    American Society for Microbiology ; 2022
    In:  Journal of Virology Vol. 96, No. 17 ( 2022-09-14)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 96, No. 17 ( 2022-09-14)
    Abstract: Herpesviruses establish latency to ensure permanent residence in their hosts. Upon entry into a cell, these viruses are rapidly silenced by the host, thereby limiting the destructive viral lytic phase while allowing the virus to hide from the immune system. Notably, although the establishment of latency by the oncogenic herpesvirus Epstein-Barr virus (EBV) requires the expression of viral latency genes, latency can be maintained with a negligible expression of viral genes. Indeed, in several herpesviruses, the host DNA sensor IFI16 facilitated latency via H3K9me3 heterochromatinization. This silencing mark is typically imposed by the constitutive heterochromatin machinery (HCM). The HCM, in an antiviral role, also silences the lytic phase of EBV and other herpes viruses. We investigated if IFI16 restricted EBV lytic activation by partnering with the HCM and found that IFI16 interacted with core components of the HCM, including the KRAB-associated protein 1 (KAP1) and the site-specific DNA binding KRAB-ZFP SZF1. This partnership silenced the EBV lytic switch protein ZEBRA, encoded by the BZLF1 gene, thereby favoring viral latency. Indeed, IFI16 contributed to H3K9 trimethylation at lytic genes of all kinetic classes. In defining topology, we found that IFI16 coenriched with KAP1 at the BZLF1 promoter, and while IFI16 and SZF1 were each adjacent to KAP1 in latent cells, IFI16 and SZF1 were not. Importantly, we also found that disruption of latency involved rapid downregulation of IFI16 transcription. These findings revealed a previously unknown partnership between IFI16 and the core HCM that supports EBV latency via antiviral heterochromatic silencing. IMPORTANCE The interferon-gamma inducible protein 16 (IFI16) is a nuclear DNA sensor that mediates antiviral responses by activating the inflammasome, triggering an interferon response, and silencing lytic genes of herpesviruses. The last, which helps maintain latency of the oncoherpesvirus Epstein-Barr virus (EBV), is accomplished via H3K9me3 heterochromatinization through unknown mechanisms. Here, we report that IFI16 physically partners with the core constitutive heterochromatin machinery to silence the key EBV lytic switch protein, thereby ensuring continued viral latency in B lymphocytes. We also find that disruption of latency involves rapid transcriptional downregulation of IFI16. These findings point to hitherto unknown physical and functional partnerships between a well-known antiviral mechanism and the core components of the constitutive heterochromatin machinery.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.01028-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
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  • 6
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    Virology under the Microscope—a Call for Rational Discourse
    American Society for Microbiology ; 2023
    In:  Journal of Virology Vol. 97, No. 2 ( 2023-02-28)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 97, No. 2 ( 2023-02-28)
    Abstract: Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.00089-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
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  • 7
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    A heterochromatin inducing protein differentially recognizes self versus foreign genomes
    Public Library of Science (PLoS) ; 2021
    In:  PLOS Pathogens Vol. 17, No. 3 ( 2021-3-17), p. e1009447-
    Details
    In: PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 3 ( 2021-3-17), p. e1009447-
    Abstract: Krüppel-associated box-domain zinc finger protein ( KRAB - ZFP ) transcriptional repressors recruit TRIM28/KAP1 to heterochromatinize the mammalian genome while also guarding the host by silencing invading foreign genomes. However, how a KRAB - ZFP recognizes target sequences in the natural context of its own or foreign genomes is unclear. Our studies on B-lymphocytes permanently harboring the cancer-causing Epstein-Barr virus (EBV) have shown that SZF1, a KRAB-ZFP, binds to several lytic/replicative phase genes to silence them, thereby promoting the latent/quiescent phase of the virus. As a result, unless SZF1 and its binding partners are displaced from target regions on the viral genome, EBV remains dormant, i.e. refractory to lytic phase-inducing triggers. As SZF1 also heterochromatinizes the cellular genome, we performed in situ footprint mapping on both viral and host genomes in physically separated B-lymphocytes bearing latent or replicative/active EBV genomes. By analyzing footprints, we learned that SZF1 recognizes the host genome through a repeat sequence-bearing motif near centromeres. Remarkably, SZF1 does not use this motif to recognize the EBV genome. Instead, it uses distinct binding sites that lack obvious similarities to each other or the above motif, to silence the viral genome. Virus mutagenesis studies show that these distinct binding sites are not only key to maintaining the established latent phase but also silencing the lytic phase in newly-infected cells, thus enabling the virus to establish latency and transform cells. Notably, these binding sites on the viral genome, when also present on the human genome, are not used by SZF1 to silence host genes during latency. This differential approach towards target site recognition may reflect a strategy by which the host silences and regulates genomes of persistent invaders without jeopardizing its own homeostasis.
    Type of Medium: Online Resource
    ISSN: 1553-7374
    URL: Article
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    DOI: 10.1371/journal.ppat.1009447
    DOI: 10.1371/journal.ppat.1009447.g001
    DOI: 10.1371/journal.ppat.1009447.g002
    DOI: 10.1371/journal.ppat.1009447.g003
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    DOI: 10.1371/journal.ppat.1009447.g008
    DOI: 10.1371/journal.ppat.1009447.t001
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    DOI: 10.1371/journal.ppat.1009447.s001
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    DOI: 10.1371/journal.ppat.1009447.s003
    DOI: 10.1371/journal.ppat.1009447.s004
    DOI: 10.1371/journal.ppat.1009447.s005
    DOI: 10.1371/journal.ppat.1009447.s006
    DOI: 10.1371/journal.ppat.1009447.s007
    DOI: 10.1371/journal.ppat.1009447.s008
    DOI: 10.1371/journal.ppat.1009447.s009
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2021
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  • 8
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    Inflammasome, the Constitutive Heterochromatin Machinery, and Replication of an Oncogenic Herpesvirus
    MDPI AG ; 2021
    In:  Viruses Vol. 13, No. 5 ( 2021-05-06), p. 846-
    Details
    In: Viruses, MDPI AG, Vol. 13, No. 5 ( 2021-05-06), p. 846-
    Abstract: The success of long-term host–virus partnerships is predicated on the ability of the host to limit the destructive potential of the virus and the virus’s skill in manipulating its host to persist undetected yet replicate efficiently when needed. By mastering such skills, herpesviruses persist silently in their hosts, though perturbations in this host–virus equilibrium can result in disease. The heterochromatin machinery that tightly regulates endogenous retroviral elements and pericentromeric repeats also silences invading genomes of alpha-, beta-, and gammaherpesviruses. That said, how these viruses disrupt this constitutive heterochromatin machinery to replicate and spread, particularly in response to disparate lytic triggers, is unclear. Here, we review how the cancer-causing gammaherpesvirus Epstein–Barr virus (EBV) uses the inflammasome as a security system to alert itself of threats to its cellular home as well as to flip the virus-encoded lytic switch, allowing it to replicate and escape in response to a variety of lytic triggers. EBV provides the first example of an infectious agent able to actively exploit the inflammasome to spark its replication. Revealing an unexpected link between the inflammasome and the epigenome, this further brings insights into how the heterochromatin machinery uses differential strategies to maintain the integrity of the cellular genome whilst guarding against invading pathogens. These recent insights into EBV biology and host–viral epigenetic regulation ultimately point to the NLRP3 inflammasome as an attractive target to thwart herpesvirus reactivation.
    Type of Medium: Online Resource
    ISSN: 1999-4915
    URL: Article
    DOI: 10.3390/v13050846
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2516098-9
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  • 9
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    Virology under the Microscope—a Call for Rational Discourse
    American Society for Microbiology ; 2023
    In:  mBio Vol. 14, No. 1 ( 2023-02-28)
    Details
    In: mBio, American Society for Microbiology, Vol. 14, No. 1 ( 2023-02-28)
    Abstract: Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mbio.00188-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 2557172-2
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  • 10
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    SARS-CoV-2 viroporin encoded by ORF3a triggers the NLRP3 inflammatory pathway
    Elsevier BV ; 2022
    In:  Virology Vol. 568 ( 2022-03), p. 13-22
    Details
    In: Virology, Elsevier BV, Vol. 568 ( 2022-03), p. 13-22
    Type of Medium: Online Resource
    ISSN: 0042-6822
    URL: Article
    DOI: 10.1016/j.virol.2022.01.003
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 200425-2
    SSG: 12
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