Parvovirus Infection-Induced DNA Damage Response

Luo, Yong; Qiu, Jianming

doi:10.2217/fvl.13.5

Cited by 42 publications

(38 citation statements)

References 132 publications

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“…They bind the viral origin of replication, nick viral DNA (56), and play an important role in inducing apoptosis and cell cycle arrest (57). However, HBoV1 NS1 is the only parvovirus NS1 protein that has been reported to activate ATM, ATR, and DNA-PKcs and to induce hallmarks of DDR (58,59). The conventional cellular response to DNA damage involves signaling events initiated by damage to the cellular genome (60).…”

Section: Discussionmentioning

confidence: 99%

“…Although HBoV1 replication in HEK293 cells induced DDR signaling, this did not trigger arrest of the cell cycle, with a high percentage of transfected cells being in S phase. In other autonomous parvoviruses, the effects of the DDR on DNA replication in dividing cells are largely due to arrest of the cell cycle (59). Infection of Walter Reed/3873D (WRD) canine cells with MVC and ex vivo-expanded human primary erythroid progenitor cells with parvovirus B19 has been shown to induce a prolonged S phase, due to the infection-induced DDR (39,40).…”

Section: Discussionmentioning

confidence: 99%

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DNA Damage Signaling Is Required for Replication of Human Bocavirus 1 DNA in Dividing HEK293 Cells

Deng

Peng

Zou

et al. 2017

J Virol

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Human bocavirus 1 (HBoV1), an emerging human-pathogenic respiratory virus, is a member of the genus Bocaparvovirus of the Parvoviridae family. In human airway epithelium air-liquid interface (HAE-ALI) cultures, HBoV1 infection initiates a DNA damage response (DDR), activating all three phosphatidylinositol 3-kinaserelated kinases (PI3KKs): ATM, ATR, and DNA-PKcs. In this context, activation of PI3KKs is a requirement for amplification of the HBoV1 genome (X. Deng, Z. Yan, F. Cheng, J. F. Engelhardt, and J. Qiu, PLoS Pathog, 12:e1005399, 2016, https://doi.org/ 10.1371/journal.ppat.1005399), and HBoV1 replicates only in terminally differentiated, nondividing cells. This report builds on the previous discovery that the replication of HBoV1 DNA can also occur in dividing HEK293 cells, demonstrating that such replication is likewise dependent on a DDR. Transfection of HEK293 cells with the duplex DNA genome of HBoV1 induces hallmarks of DDR, including phosphorylation of H2AX and RPA32, as well as activation of all three PI3KKs. The large viral nonstructural protein NS1 is sufficient to induce the DDR and the activation of the three PI3KKs. Pharmacological inhibition or knockdown of any one of the PI3KKs significantly decreases both the replication of HBoV1 DNA and the downstream production of progeny virions. The DDR induced by the HBoV1 NS1 protein does not cause obvious damage to cellular DNA or arrest of the cell cycle. Notably, key DNA replication factors and major DNA repair DNA polymerases (polymerase [Pol ] and polymerase [Pol ]) are recruited to the viral DNA replication centers and facilitate HBoV1 DNA replication. Our study provides the first evidence of the DDR-dependent parvovirus DNA replication that occurs in dividing cells and is independent of cell cycle arrest.IMPORTANCE The parvovirus human bocavirus 1 (HBoV1) is an emerging respiratory virus that causes lower respiratory tract infections in young children worldwide. HEK293 cells are the only dividing cells tested that fully support the replication of the duplex genome of this virus and allow the production of progeny virions. In this study, we demonstrate that HBoV1 induces a DDR that plays significant roles in the replication of the viral DNA and the production of progeny virions in HEK293 cells. We also show that both cellular DNA replication factors and DNA repair DNA polymerases colocalize within centers of viral DNA replication and that Pol and Pol play an important role in HBoV1 DNA replication. Whereas the DDR that leads to the replication of the DNA of other parvoviruses is facilitated by the cell cycle, the DDR triggered by HBoV1 DNA replication or NS1 is not. HBoV1 is the first parvovirus whose NS1 has been shown to be able to activate all three PI3KKs (ATM, ATR, and DNA-PKcs).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DNA Damage Signaling Is Required for Replication of Human Bocavirus 1 DNA in Dividing HEK293 Cells

Deng

Peng

Zou

et al. 2017

J Virol

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“…The oxidant/antioxidant imbalance has been reported in pathogenesis of enteric viral diseases like feline coronavirus, bovine herpesvirus‐1, porcine reproductive and respiratory syndrome and rotavirus (De et al., ; Durgut, Ataseven, & Öztürk, ; Kayar et al., ; Stukelj, Toplak, & Nemec Svete, ). Recently, it has been observed that parvovirus infection is linked with oxidative stress, and marked enhancement of reactive oxygen/nitrogen species, lipid peroxidation, DNA damage and poor antioxidant reserve (Luo & Qiu, ; Nykky, Vuento, & Gilbert, ; Panda, Patra, Nandi, & Swarup, ). In recent years, emphasis has been given on the antioxidants as the potential drugs of interest for management of viral diseases (Beck, ; Chandrasena et al., ; Crump, Langston, Rajkarnikar, & Grayson, ).…”

Section: Introductionmentioning

confidence: 99%

Amelioration of oxidative stress using N‐acetylcysteine in canine parvoviral enteritis

Gaykwad

Garkhal

Chethan

et al. 2017

Vet Pharm & Therapeutics

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Previously, antioxidants have not been evaluated for treatment of parvoviral diarrhea in dogs. In this study, antioxidant potential of N-acetylcysteine (NAC) in dogs infected with canine parvovirus with a nonblinded randomized clinical trial has been carried out. A total 18 parvo-infected dogs were randomly divided into two groups: nine parvo-infected dogs were treated with supportive treatment and nine parvo-infected dogs were treated with NAC along with supportive treatment. Simultaneously, nine healthy dogs were kept as healthy control. In parvo-infected dogs, marked hemoconcentration, leucopenia, neutropenia and oxidative stress were noticed compared to healthy dogs. The NAC treatment progressively improved the leukocyte, neutrophil, monocyte, and eosinophil counts over the time in parvovirus-infected dogs compared to dogs that received only supportive treatment. In addition, NAC treatment significantly improved glutathione S-transferase (GST) activity and decreased nitrite plus nitrate (NOx) and malondialdehyde (MDA) concentrations on day 3 and 5 compared to supportive treatment in parvo-infected dogs. However, supportive treatment alone failed to ameliorate oxidative stress in the infected dogs till day 5. The results of this study suggest that NAC represents a potential additional treatment option that could be considered to improve the health condition and minimize the duration of hospitalization in case of canine parvoviral diarrhea.

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“…Furthermore, phosphorylation of Nups can occur in response to DNA damage, commonly detected in parvovirus infections (26,27), and can indicate an infection-induced functional change of Nup153 (28,29). Our analyses do not exclude the possibility of Nup153 becoming detached from the NPCs in infection.…”

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confidence: 70%

Reorganization of Nuclear Pore Complexes and the Lamina in Late-Stage Parvovirus Infection

Mäntylä

Niskanen

Ihalainen

et al. 2015

J Virol

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c Canine parvovirus (CPV) infection induces reorganization of nuclear structures. Our studies indicated that late-stage infection induces accumulation of nuclear pore complexes (NPCs) and lamin B1 concomitantly with a decrease of lamin A/C levels on the apical side of the nucleus. Newly formed CPV capsids are located in close proximity to NPCs on the apical side. These results suggest that parvoviruses cause apical enrichment of NPCs and reorganization of nuclear lamina, presumably to facilitate the late-stage infection. The nuclear lamina is a protein-rich structural scaffold, the main components of which are the dynamic type V intermediate filament proteins called lamins. Lamin proteins comprise two subtypes, type A (lamin A, A10, C, and C2) and type B (B1, B2, and B3). The former are alternative splice products of the LMNA gene, and the latter are encoded by LMNB1 (B1) and LMNB2 (B2 and germ line-specific B3) genes (1). In structure, the lamins of both subtypes contain a central ␣-helical rod with globular head (N) and tail (C) domains. In vitro, the lamins dimerize in a parallel fashion followed by filament assembly (2, 3). The lamina is connected to the cytoskeleton via the nuclear envelope (NE)-spanning linker of nucleoskeleton and cytoskeleton (LINC) complex (4). Lamina also interacts with nuclear pore complexes (NPCs) consisting of ϳ30 nucleoporins (Nups) and regulating bidirectional transport of molecules over the NE (5). Together, the NPCs and lamina define a dynamic barrier that mediates signals in response to cellular stress conditions such as virus infections and limits release of viral progeny after nuclear assembly (6-9). To overcome this barrier, viruses are known to alter the architecture of all aforementioned subnuclear structures, which in turn contribute to the function of the nucleus (10). Nuclear egress of parvovirus (PV) capsids has been suggested to occur by active export via the NPC pathway prior to cell lysis (11-13). However, the influence of parvovirus egress on the organization of NPCs and nuclear lamina is unknown. Here, we examined the distribution and organization of NPCs as well as A and B type lamins in canine parvovirus (CPV)-infected cells in late infection in comparison with those in noninfected S-and G-phase (G 1 /G 2 ) cells.The NPCs are dynamic structures capable of assembly, disassembly, and redistribution during the cell cycle (14, 15). The nucleus has a spatially polarized architecture (16); however, the NPC distributions between the apical and basal sides of the nucleus have not been comparatively determined. Here, we examined the spatial distributions of NPCs at the apical and basal sides of nuclei in CPV-infected (multiplicity of infection [MOI] of 1 at 24 h postinfection [p.i.]) and mock-infected S-or G 1 /G 2 -phase Norden laboratory feline kidney (NLFK) cells. The NPCs were immunostained with a nucleoporin 153 (Nup153) antibody (Ab) (ab24700; Abcam, Cambridge, United Kingdom) also recognizing Nup62. A proliferating cell nuclear antigen (PCNA) Ab (ab18197; Abcam, C...

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Parvovirus Infection-Induced DNA Damage Response

Cited by 42 publications

References 132 publications

DNA Damage Signaling Is Required for Replication of Human Bocavirus 1 DNA in Dividing HEK293 Cells

DNA Damage Signaling Is Required for Replication of Human Bocavirus 1 DNA in Dividing HEK293 Cells

Amelioration of oxidative stress using N‐acetylcysteine in canine parvoviral enteritis

Reorganization of Nuclear Pore Complexes and the Lamina in Late-Stage Parvovirus Infection

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