Polyomavirus interaction with the DNA damage response

Justice, Joshua; Verhalen, Brandy; Jiang, Mengxi

doi:10.1007/s12250-015-3583-6

Cited by 16 publications

(19 citation statements)

References 51 publications

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“…Thus, DDR proteins may be considered common components of VRCs. While some DDR pathways are antagonized by DNA viruses to prevent the DDR from attenuating infection, others are activated by viruses to promote viral processes [8][9][10]124,125]. However, exactly how cellular DNA repair and DNA replication factors are harnessed to promote viral processes is often unclear.…”

Section: The Composition Of Replication Compartmentsmentioning

confidence: 99%

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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Section: The Composition Of Replication Compartmentsmentioning

confidence: 99%

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

Charman

Weitzman

2020

Viruses

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“…Together, these oncogenes commandeer the host cell, promote S-phase entry, and induce multiple rounds of viral and host chromatin replication (7). In addition to promoting S phase, all studied PyVs activate the DNA damage response (DDR) during infection, which is required for efficient amplification of the viral genome, production of virions, and protection of the host from severe DNA damage linked to infection (7)(8)(9).…”

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confidence: 99%

BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase

Justice

Needham

Thompson

2019

J Virol

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BK polyomavirus (PyV) is a major source of kidney failure in transplant recipients. The standard treatment for patients with lytic BKPyV infection is to reduce immunosuppressive therapy, which increases the risk of graft rejection. PyVs are DNA viruses that rely upon host replication proteins for viral genome replication. A hallmark of PyV infection is activation of the DNA damage response (DDR) to prevent severe host and viral DNA damage that impairs viral production by an unknown mechanism. Therefore, we sought to better understand why BKPyV activates the DDR through the ATR and ATM pathways and how this prevents DNA damage and leads to increased viral production. When ATR was inhibited in BKPyV-infected primary kidney cells, severe DNA damage occurred due to premature Cdk1 activation, which resulted in mitosis of cells that were actively replicating host DNA in S phase. Conversely, ATM was required for efficient entry into S phase and to prevent normal mitotic entry after G 2 phase. The synergistic activation of these DDR kinases promoted and maintained BKPyV-mediated S phase to enhance viral production. In contrast to BKPyV infection, DDR inhibition did not disrupt cell cycle control in uninfected cells. This suggests that DDR inhibitors may be used to specifically target BKPyV-infected cells. IMPORTANCE BK polyomavirus (BKPyV) is an emerging pathogen that reactivates in immunosuppressed organ transplant patients. We wanted to understand why BKPyV-induced activation of the DNA damage response (DDR) enhances viral titers and prevents host DNA damage. Here, we show that the virus activates the DNA damage response in order to keep the infected cells in S phase to replicate the viral DNA. The source of DNA damage was due to actively replicating cells with uncondensed chromosomes entering directly into mitosis when the DDR was inhibited in BKPyV-infected cells. This study clarifies the previously enigmatic role of the DDR during BKPyV infection by demonstrating that the virus activates the DDR to maintain the cells in S phase in order to promote viral replication and that disruption of this cell cycle arrest can lead to catastrophic DNA damage for the host.

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“…Even though many viruses can cause different tumors in animals, only seven of them are linked with human cancers and are presently regard as oncogenic viruses. These viruses include Human Papillomavirus (HPV), Hepatitis B (HBV) and Hepatitis C Virus (HCV) [22], Epstein Barr Virus (EBV) [23], Human Herpesvirus-8 (HHV8) [24], Human T-cell Leukemia Virus (HTLV) [25] and Merkel Cell Polyomavirus (MCPyV) [26]. There are various mechanisms by which these viruses transformed normal cells into tumor cells [27].…”

Section: Oncogenic Viral Infectionsmentioning

confidence: 99%

“…Hepatitis B or C. Epidemiological studies revealed that there is a strong association between HBV with liver cancer [30]. MCPyV can cause Merkel cell tumor [26] and HTLV-1 causes adult T-cell lymphoma. HHV8 (also known as Kaposi's sarcoma-linked Herpesvirus, KSHV) has been dependable for Kaposi's sarcoma generally found in patients with acquired immunodeficiency syndrome (AIDS) [24] (Tables 4 and 5)…”

Section: Oncogenic Viral Infectionsmentioning

confidence: 99%

Circulating microRNAs in oncogenic viral infections: potential diagnostic biomarkers

2020

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Cancer is a leading cause of high death rate worldwide. One strategy to control the disease is the early diagnosis by novel biomarkers that express during early stage of the disease. The recent diagnostic strategies in cancer don't have enough specificity to promote the detection of cancer at its beginning. Many biomarkers like protein biomarkers and metabolites are being used for diagnosis of various cancer types but miRNAs are excellent among them, because they have distinctive biochemical characteristics. Moreover, to raise the precision and capability of miRNA to diagnose cancer, the analyzing of both miRNAs and as well as selective mRNA will help in creating a more complete categorizer. Virus constitutes the cause of 20% of entire human cancer cases and both RNA and DNA viruses are linked with tumors in both animal and man. Even though many viruses can cause different tumors in animals, only some of them are linked with human cancers and are presently regarded as oncogenic viruses. These viruses include Human Papillomavirus (HPV), Hepatitis B (HBV) and Hepatitis C Virus (HCV), Epstein Barr Virus (EBV), Human Herpes Virus 8 (HHV8), Human T cell Leukemia Virus (HTLV) and Merkel Cell Polyomavirus (MCPyV). Expression data of miRNA in several cancers reveal that miRNA profile is different in cancer cells as compared to normal cells. So, miRNA could be useful biomarker for the detection of cancer. The present study strengthens a foundation and gives a logic to investigate the ability of miRNAs as circulating biomarkers in various cancers.

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Polyomavirus interaction with the DNA damage response

Cited by 16 publications

References 51 publications

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

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

BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase

Circulating microRNAs in oncogenic viral infections: potential diagnostic biomarkers

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