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Open AccessArticle

Characterization of the EBV-Induced Persistent DNA Damage Response

by Amy Y. Hafez and Micah A. Luftig

Viruses 2017, 9(12), 366; https://doi.org/10.3390/v9120366 - 01 Dec 2017

Cited by 13 | Viewed by 6508

Epstein-Barr virus (EBV) is an oncogenic herpesvirus that is ubiquitous in the human population. Early after EBV infection in vitro, primary human B cells undergo a transient period of hyper-proliferation, which results in replicative stress and DNA damage, activation of the DNA damage [...] Read more.

Epstein-Barr virus (EBV) is an oncogenic herpesvirus that is ubiquitous in the human population. Early after EBV infection in vitro, primary human B cells undergo a transient period of hyper-proliferation, which results in replicative stress and DNA damage, activation of the DNA damage response (DDR) pathway and, ultimately, senescence. In this study, we investigated DDR-mediated senescence in early arrested EBV-infected B cells and characterized the establishment of persistent DNA damage foci. We found that arrested EBV-infected B cells exhibited an increase in promyelocytic leukemia nuclear bodies (PML NBs), which predominantly localized to markers of DNA damage, as well as telomeric DNA. Furthermore, arrested EBV-infected B cells exhibited an increase in the presence of telomere dysfunction-induced foci. Importantly, we found that increasing human telomerase reverse transcriptase (hTERT) expression with danazol, a drug used to treat telomere diseases, permitted early EBV-infected B cells to overcome cellular senescence and enhanced transformation. Finally, we report that EBV-infected B cells undergoing hyper-proliferation are more sensitive than lymphoblastoid cell lines (LCLs) to inhibition of Bloom syndrome-associated helicase, which facilitates telomere replication. Together, our results describe the composition of persistent DNA damage foci in the early stages of EBV infection and define key regulators of this barrier to long-term outgrowth. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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3245 KiB

Open AccessArticle

The Non-Homologous End Joining Protein PAXX Acts to Restrict HSV-1 Infection

by Ben J. Trigg, Katharina B. Lauer, Paula Fernandes dos Santos, Heather Coleman, Gabriel Balmus, Daniel S. Mansur and Brian J. Ferguson

Viruses 2017, 9(11), 342; https://doi.org/10.3390/v9110342 - 16 Nov 2017

Cited by 8 | Viewed by 6770

Abstract

Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral [...] Read more.

Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral genome, while different members of the classical non-homologous end-joining (c-NHEJ) pathway have opposing effects on HSV-1 infection. Here, we have investigated the role of the recently-discovered c-NHEJ component, PAXX (Paralogue of XRCC4 and XLF), which we found to be excluded from the nucleus during HSV-1 infection. We have established that cells lacking PAXX have an intact innate immune response to HSV-1 but show a defect in viral genome replication efficiency. Counterintuitively, PAXX^−/− cells were able to produce greater numbers of infectious virions, indicating that PAXX acts to restrict HSV-1 infection in a manner that is different from other c-NHEJ factors. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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Open AccessArticle

LEDGF/p75 Deficiency Increases Deletions at the HIV-1 cDNA Ends

by Murilo T. D. Bueno, Daniel Reyes and Manuel Llano

Viruses 2017, 9(9), 259; https://doi.org/10.3390/v9090259 - 15 Sep 2017

Cited by 1 | Viewed by 3904

Abstract

Processing of unintegrated linear HIV-1 cDNA by the host DNA repair system results in its degradation and/or circularization. As a consequence, deficient viral cDNA integration generally leads to an increase in the levels of HIV-1 cDNA circles containing one or two long terminal [...] Read more.

Processing of unintegrated linear HIV-1 cDNA by the host DNA repair system results in its degradation and/or circularization. As a consequence, deficient viral cDNA integration generally leads to an increase in the levels of HIV-1 cDNA circles containing one or two long terminal repeats (LTRs). Intriguingly, impaired HIV-1 integration in LEDGF/p75-deficient cells does not result in a correspondent increase in viral cDNA circles. We postulate that increased degradation of unintegrated linear viral cDNA in cells lacking the lens epithelium-derived growth factor (LEDGF/p75) account for this inconsistency. To evaluate this hypothesis, we characterized the nucleotide sequence spanning 2-LTR junctions isolated from LEDGF/p75-deficient and control cells. LEDGF/p75 deficiency resulted in a significant increase in the frequency of 2-LTRs harboring large deletions. Of note, these deletions were dependent on the 3′ processing activity of integrase and were not originated by aberrant reverse transcription. Our findings suggest a novel role of LEDGF/p75 in protecting the unintegrated 3′ processed linear HIV-1 cDNA from exonucleolytic degradation. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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Review

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How Human Papillomavirus Replication and Immune Evasion Strategies Take Advantage of the Host DNA Damage Repair Machinery

by Valentina Bordignon, Enea Gino Di Domenico, Elisabetta Trento, Giovanna D’Agosto, Ilaria Cavallo, Martina Pontone, Fulvia Pimpinelli, Luciano Mariani and Fabrizio Ensoli

Viruses 2017, 9(12), 390; https://doi.org/10.3390/v9120390 - 19 Dec 2017

Cited by 39 | Viewed by 11755

Abstract

The DNA damage response (DDR) is a complex signalling network activated when DNA is altered by intrinsic or extrinsic agents. DDR plays important roles in genome stability and cell cycle regulation, as well as in tumour transformation. Viruses have evolved successful life cycle [...] Read more.

The DNA damage response (DDR) is a complex signalling network activated when DNA is altered by intrinsic or extrinsic agents. DDR plays important roles in genome stability and cell cycle regulation, as well as in tumour transformation. Viruses have evolved successful life cycle strategies in order to ensure a chronic persistence in the host, virtually avoiding systemic sequelae and death. This process promotes the periodic shedding of large amounts of infectious particles to maintain a virus reservoir in individual hosts, while allowing virus spreading within the community. To achieve such a successful lifestyle, the human papilloma virus (HPV) needs to escape the host defence systems. The key to understanding how this is achieved is in the virus replication process that provides by itself an evasion mechanism by inhibiting and delaying the host immune response against the viral infection. Numerous studies have demonstrated that HPV exploits both the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3-related (ATR) DDR pathways to replicate its genome and maintain a persistent infection by downregulating the innate and cell-mediated immunity. This review outlines how HPV interacts with the ATM- and ATR-dependent DDR machinery during the viral life cycle to create an environment favourable to viral replication, and how the interaction with the signal transducers and activators of transcription (STAT) protein family and the deregulation of the Janus kinase (JAK)–STAT pathways may impact the expression of interferon-inducible genes and the innate immune responses. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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Open AccessReview

Epstein–Barr Virus Hijacks DNA Damage Response Transducers to Orchestrate Its Life Cycle

by Pok Man Hau and Sai Wah Tsao

Viruses 2017, 9(11), 341; https://doi.org/10.3390/v9110341 - 16 Nov 2017

Cited by 36 | Viewed by 8215

Abstract

The Epstein–Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt’s lymphoma, Hodgkin’s lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has [...] Read more.

The Epstein–Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt’s lymphoma, Hodgkin’s lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has shown that EBV triggers a DNA damage response (DDR) during primary infection and lytic reactivation. The EBV-encoded viral proteins have been implicated in deregulating the DDR signaling pathways. The consequences of DDR inactivation lead to genomic instability and promote cellular transformation. This review summarizes the current understanding of the relationship between EBV infection and the DDR transducers, including ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), and DNA-PK (DNA-dependent protein kinase), and discusses how EBV manipulates the DDR signaling pathways to complete the replication process of viral DNA during lytic reactivation. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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Hepatitis B Virus and DNA Damage Response: Interactions and Consequences for the Infection

by Andoni Gómez-Moreno and Urtzi Garaigorta

Viruses 2017, 9(10), 304; https://doi.org/10.3390/v9100304 - 19 Oct 2017

Cited by 25 | Viewed by 10907

Abstract

Hepatitis B virus (HBV) is a major etiologic agent of acute and chronic hepatitis, and end-stage liver disease. Establishment of HBV infection, progression to persistency and pathogenesis are determined by viral and cellular factors, some of which remain still undefined. Key steps of [...] Read more.

Hepatitis B virus (HBV) is a major etiologic agent of acute and chronic hepatitis, and end-stage liver disease. Establishment of HBV infection, progression to persistency and pathogenesis are determined by viral and cellular factors, some of which remain still undefined. Key steps of HBV life cycle e.g., transformation of genomic viral DNA into transcriptionally active episomal DNA (cccDNA) or transcription of viral mRNAs from cccDNA, take place in the nucleus of infected cells and strongly depend on enzymatic activities provided by cellular proteins. In this regard, DNA damage response (DDR) pathways and some DDR proteins are being recognized as important factors regulating the infection. On one hand, HBV highjacks specific DDR proteins to successfully complete some of the steps of its life cycle. On the other hand, HBV subverts DDR pathways to presumably create a cellular environment that favours its replication. Direct consequences of these interactions are: HBV DNA integration into host chromosomal DNA, and accumulation of mutations in host chromosomal DNA that could eventually trigger carcinogenic processes, which would explain in part the incidence of hepatocellular carcinoma in chronically infected patients. Unravelling the interactions that HBV establishes with DDR pathways might help identify new molecular targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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Open AccessReview

Why Human Papillomaviruses Activate the DNA Damage Response (DDR) and How Cellular and Viral Replication Persists in the Presence of DDR Signaling

by Molly L. Bristol, Dipon Das and Iain M. Morgan

Viruses 2017, 9(10), 268; https://doi.org/10.3390/v9100268 - 21 Sep 2017

Cited by 37 | Viewed by 6864

Abstract

Human papillomaviruses (HPV) require the activation of the DNA damage response (DDR) in order to undergo a successful life cycle. This activation presents a challenge for the virus and the infected cell: how does viral and host replication proceed in the presence of [...] Read more.

Human papillomaviruses (HPV) require the activation of the DNA damage response (DDR) in order to undergo a successful life cycle. This activation presents a challenge for the virus and the infected cell: how does viral and host replication proceed in the presence of a DDR that ordinarily arrests replication; and how do HPV16 infected cells retain the ability to proliferate in the presence of a DDR that ordinarily arrests the cell cycle? This raises a further question: why do HPV activate the DDR? The answers to these questions are only partially understood; a full understanding could identify novel therapeutic strategies to target HPV cancers. Here, we propose that the rapid replication of an 8 kb double stranded circular genome during infection creates aberrant DNA structures that attract and activate DDR proteins. Therefore, HPV replication in the presence of an active DDR is a necessity for a successful viral life cycle in order to resolve these DNA structures on viral genomes; without an active DDR, successful replication of the viral genome would not proceed. We discuss the essential role of TopBP1 in this process and also how viral and cellular replication proceeds in HPV infected cells in the presence of DDR signals. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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Open AccessReview

Human Papillomavirus and the DNA Damage Response: Exploiting Host Repair Pathways for Viral Replication

by Chelsey C. Spriggs and Laimonis A. Laimins

Viruses 2017, 9(8), 232; https://doi.org/10.3390/v9080232 - 18 Aug 2017

Cited by 50 | Viewed by 8179

Abstract

High-risk human papillomaviruses (HPVs) are the causative agents of cervical and other genital cancers. In addition, HPV infections are associated with the development of many oropharyngeal cancers. HPVs activate and repress a number of host cellular pathways to promote their viral life cycles, [...] Read more.

High-risk human papillomaviruses (HPVs) are the causative agents of cervical and other genital cancers. In addition, HPV infections are associated with the development of many oropharyngeal cancers. HPVs activate and repress a number of host cellular pathways to promote their viral life cycles, including those of the DNA damage response. High-risk HPVs activate the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) DNA damage repair pathways, which are essential for viral replication (particularly differentiation-dependent genome amplification). These DNA repair pathways are critical in maintaining host genomic integrity and stability and are often dysregulated or mutated in human cancers. Understanding how these pathways contribute to HPV replication and transformation may lead to the identification of new therapeutic targets for the treatment of existing HPV infections. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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