Viral replication centers and the DNA damage response in JC virus-infected cells

Erickson, Kimberly D.; Garcea, Robert L.

doi:10.1016/j.virol.2018.12.014

Cited by 24 publications

(25 citation statements)

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“…Previous immuno-electron microscopy of JCV-infected SVG-A cells described a close spatial relationship between VRCs and assembled virions [51], and a similar relationship was observed during MuPyV infection [7]. The spatial coordination of these processes presumably enhances infection by accumulating and maintaining cellular and viral factors adjacent to sites of vDNA synthesis.…”

Section: Plos Pathogensmentioning

confidence: 67%

“…Although FISH identified vDNA at DDR-associated focal RPA32 (Figs 1 and 2), the trafficking of vDNA between VRC subdomains was unclear. EdU labels replicating vDNA within PyV replication centers [8,51,52], so we applied pulse-chase labeling with EdU to identify discrete subpopulations of vDNA at different times post-synthesis ( Fig 3A). The EdU signal immediately after the pulse label (nascent vDNA) localized within VRCs and overlapped with LT, suggesting this subdomain represented the initial site of vDNA synthesis ( Fig 3B and S3A Fig).…”

Section: Nascent Mupyv Dna Rapidly Dissociates From Ltmentioning

confidence: 99%

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Murine polyomavirus DNA transitions through spatially distinct nuclear replication subdomains during infection

Peters

Garcea

2020

PLoS Pathog

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The replication of small DNA viruses requires both host DNA replication and repair factors that are often recruited to subnuclear domains termed viral replication centers (VRCs). Aside from serving as a spatial focus for viral replication, little is known about these dynamic areas in the nucleus. We investigated the organization and function of VRCs during murine polyomavirus (MuPyV) infection using 3D structured illumination microscopy (3D-SIM). We localized MuPyV replication center components, such as the viral large T-antigen (LT) and the cellular replication protein A (RPA), to spatially distinct subdomains within VRCs. We found that viral DNA (vDNA) trafficked sequentially through these subdomains post-synthesis, suggesting their distinct functional roles in vDNA processing. Additionally, we observed disruption of VRC organization and vDNA trafficking during mutant MuPyV infections or inhibition of DNA synthesis. These results reveal a dynamic organization of VRC components that coordinates virus replication.

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Section: Plos Pathogensmentioning

confidence: 67%

Section: Nascent Mupyv Dna Rapidly Dissociates From Ltmentioning

confidence: 99%

Murine polyomavirus DNA transitions through spatially distinct nuclear replication subdomains during infection

Peters

Garcea

2020

PLoS Pathog

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“…Electron microscopy of MPyV and JCV-infected cells reveal accumulated virions and adjacent tubular structures that appear to be assembly intermediates from which assembling virions "bud". These virions and tubular structures localized to inter-chromosomal spaces that stain positive for PML and VP1, suggesting that polyomavirus VRCs are the sites of active capsid assembly [55,163]. In the case of papillomaviruses, although the spatial organization of capsid assembly and packaging is not well understood, a number of studies have identified the localization of L1 major and L2 minor capsid protein at VRCs similarly to the localization of polyomavirus capsid proteins [137,152,164].…”

Section: Virion Production At Replication Compartmentsmentioning

confidence: 97%

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

Charman

Weitzman

2020

Viruses

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DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These viruses must co-opt nuclear processes for the benefit of the virus, whilst evading host processes that would otherwise attenuate viral replication. Accordingly, DNA viruses induce the formation of membraneless assemblies termed viral replication compartments (VRCs). These compartments facilitate the spatial organization of viral processes and regulate virus-host interactions. Here, we review advances in our understanding of VRCs. We cover their initiation and formation, their function as the sites of viral processes, and aspects of their composition and organization. In doing so, we highlight ongoing and emerging areas of research highly pertinent to our understanding of nuclear-replicating DNA viruses.Viruses 2020, 12, 151 2 of 20 The Initiation and Formation of Replication CompartmentsDNA viruses that replicate in the nucleus exhibit a diverse array of strategies to complete their replication cycle and ultimately produce progeny virions. Despite their many differences, the strategies employed by DNA viruses to initiate productive infection and establish VRCs share many features in common. Indeed, it is likely that all DNA viruses that replicate in the nucleus form VRCs. Following penetration of the host cell and the transport of viral capsids/cores, viral DNA genomes enter the nucleus, where they begin a program of temporally regulated gene expression that initiates productive infection [1,2]. Early gene products include viral proteins required to manipulate the host-cell environment and replicate the viral genome. Viral replication proteins interact with the viral genome and initiate genome replication leading to VRC formation, which is often in concert with certain co-opted host proteins. However, these viruses must overcome several challenges to form VRCs successfully. Firstly, incoming genomes must avoid cellular intrinsic antiviral defenses and homeostatic regulatory pathways such as elements of the DNA damage response (DDR) that respond to the presence of foreign DNA and act to suppress viral gene expression [3][4][5][6][7][8][9][10]. Secondly, VRCs typically form at specific sites within the nucleus, suggesting that viral genomes need to be targeted to these sites in order to initiate VRC formation [6,11,12]. Furthermore, it has been hypothesized that the formation and growth of VRCs may require manipulation of the nuclear environment and the re-organization of host chromatin to overcome the spatial restraints of the nucleus [11][12][13][14][15]. In this section, we review key features of VRC initiation and highlight some major challenges to VRC formation. Interplay between Viral Replication Compartment Formation and Promyelocytic Leukemia Protein Nuclear BodiesA common theme amongst many nuclear-replicating DNA viruses is initiation of VRCs at sites in close proximity to promyelocytic leukemia protein (PML) nuclear bodies (NBs). Since the dis...

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“…This dysregulation of LTAg expression in non-lytic cells might drive cell growth, DNA damage, and tumorigenesis [ 117 ]. In the case of JCV, we and others have reported the activation of DNA damage response during JCV infection or transient expression of LTAg which is associated with activation of ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-Related (ATR) kinases [ 118 , 119 ]. This molecular interaction of JCV with the components of the DDR facilitate conditions that promote viral replication at the cost of host genomic instability that may lead to tumorigenicity [ 120 ].…”

Section: Jcv Early Gene Products and Agno Protein And Their Oncogementioning

confidence: 99%

The Role of the JC Virus in Central Nervous System Tumorigenesis

Ahye

Bellizzi

May

et al. 2020

IJMS

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Cancer is the second leading cause of mortality worldwide. The study of DNA tumor-inducing viruses and their oncoproteins as a causative agent in cancer initiation and tumor progression has greatly enhanced our understanding of cancer cell biology. The initiation of oncogenesis is a complex process. Specific gene mutations cause functional changes in the cell that ultimately result in the inability to regulate cell differentiation and proliferation effectively. The human neurotropic Polyomavirus JC (JCV) belongs to the family Polyomaviridae and it is the causative agent of progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease in an immunosuppressed state. Sero-epidemiological studies have indicated JCV infection is prevalent in the population (85%) and that initial infection usually occurs during childhood. The JC virus has small circular, double-stranded DNA that includes coding sequences for viral early and late proteins. Persistence of the virus in the brain and other tissues, as well as its potential to transform cells, has made it a subject of study for its role in brain tumor development. Earlier observation of malignant astrocytes and oligodendrocytes in PML, as well as glioblastoma formation in non-human primates inoculated with JCV, led to the hypothesis that JCV plays a role in central nervous system (CNS) tumorigenesis. Some studies have reported the presence of both JC viral DNA and its proteins in several primary brain tumor specimens. The discovery of new Polyomaviruses such as the Merkel cell Polyomavirus, which is associated with Merkel cell carcinomas in humans, ignited our interest in the role of the JC virus in CNS tumors. The current evidence known about JCV and its effects, which are sufficient to produce tumors in animal models, suggest it can be a causative factor in central nervous system tumorigenesis. However, there is no clear association between JCV presence in CNS and its ability to initiate CNS cancer and tumor formation in humans. In this review, we will discuss the correlation between JCV and tumorigenesis of CNS in animal models, and we will give an overview of the current evidence for the JC virus’s role in brain tumor formation.

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Viral replication centers and the DNA damage response in JC virus-infected cells

Cited by 24 publications

References 51 publications

Murine polyomavirus DNA transitions through spatially distinct nuclear replication subdomains during infection

Murine polyomavirus DNA transitions through spatially distinct nuclear replication subdomains during infection

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

The Role of the JC Virus in Central Nervous System Tumorigenesis

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