Manipulation of PML Nuclear Bodies and DNA Damage Responses by DNA Viruses

Frappier, Lori

doi:10.1007/978-3-319-38882-3_13

Cited by 3 publications

(3 citation statements)

References 190 publications

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“…We note that As 2 O 3 has been shown to induce oxidative stress, DNA damage, and mitochondrial stress, and these pathways may be important for the effects on late viral gene expression [ 31 , 32 ]. We should note that several EBV lytic genes (BZLF1, BRLF1, BGLF4) disrupt PML nuclear bodies through PML dispersal [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Arsenicals, the Integrated Stress Response, and Epstein–Barr Virus Lytic Gene Expression

Lee

Stone

Desai

et al. 2021

Viruses

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Following our observation that clofoctol led to Epstein–Barr virus (EBV) lytic gene expression upon activation of the integrated stress response (ISR), we decided to investigate the impact of As2O3 on viral lytic gene expression. As2O3 has also been reported to activate the ISR pathway by its activation of the heme-regulated inhibitor (HRI). Our investigations show that As2O3 treatment leads to eIF2α phosphorylation, upregulation of ATF4 and TRB3 expression, and an increase of EBV Zta gene expression in lymphoid tumor cell lines as well as in naturally infected epithelial cancer cell lines. However, late lytic gene expression and virion production were blocked after arsenic treatment. In comparison, a small molecule HRI activator also led to increased Zta expression but did not block late lytic gene expression, suggesting that As2O3 effects on EBV gene expression are also mediated through other pathways.

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Section: Discussionmentioning

confidence: 99%

Arsenicals, the Integrated Stress Response, and Epstein–Barr Virus Lytic Gene Expression

Lee

Stone

Desai

et al. 2021

Viruses

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“…Life-long infection occurs due to the ability of EBV to alternate between latent modes of infection, with restricted viral gene expression, and lytic infection involving expression of an additional ~70 viral proteins. Together, these lytic proteins manipulate many cellular processes including innate immune responses, cell cycle progression and DNA damage responses, in order to promote cell survival and virion production [ 27 , 28 ]. However, the functions of many EBV lytic proteins are unknown and even proteins with an assigned function may have additional unidentified roles.…”

Section: Introductionmentioning

confidence: 99%

A genome-wide screen of Epstein-Barr virus proteins that modulate host SUMOylation identifies a SUMO E3 ligase conserved in herpesviruses

et al. 2018

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Many cellular processes pertinent for viral infection are regulated by the addition of small ubiquitin-like modifiers (SUMO) to key regulatory proteins, making SUMOylation an important mechanism by which viruses can commandeer cellular pathways. Epstein-Barr virus (EBV) is a master at manipulating of cellular processes, which enables life-long infection but can also lead to the induction of a variety of EBV-associated cancers. To identify new mechanisms by which EBV proteins alter cells, we screened a library of 51 EBV proteins for global effects on cellular SUMO1 and SUMO2 modifications (SUMOylation), identifying several proteins not previously known to manipulate this pathway. One EBV protein (BRLF1) globally induced the loss of SUMOylated proteins, in a proteasome-dependent manner, as well as the loss of promeylocytic leukemia nuclear bodies. However, unlike its homologue (Rta) in Kaposi’s sarcoma associated herpesvirus, it did not appear to have ubiquitin ligase activity. In addition we identified the EBV SM protein as globally upregulating SUMOylation and showed that this activity was conserved in its homologues in herpes simplex virus 1 (HSV1 UL54/ICP27) and cytomegalovirus (CMV UL69). All three viral homologues were shown to bind SUMO and Ubc9 and to have E3 SUMO ligase activity in a purified system. These are the first SUMO E3 ligases discovered for EBV, HSV1 and CMV. Interestingly the homologues had different specificities for SUMO1 and SUMO2, with SM and UL69 preferentially binding SUMO1 and inducing SUMO1 modifications, and UL54 preferentially binding SUMO2 and inducing SUMO2 modifications. The results provide new insights into the function of this family of conserved herpesvirus proteins, and the conservation of this SUMO E3 ligase activity across diverse herpesviruses suggests the importance of this activity for herpesvirus infections.

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“…EBV and herpesviruses in general have a complicated relationship with the cellular DNA damage response (DDR), both activating and inactivating different steps in the response (7)(8)(9)(10). The cell responds to DNA double-strand breaks (DSBs) by a cascade of events beginning with MRE11-RAD50-NBS1 (MRN) binding to the double-stranded DNA (dsDNA) break, which recruits and activates ATM, a phosphatidylinositol 3-kinase (PI3K) protein kinase.…”

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confidence: 99%

A Screen for Epstein-Barr Virus Proteins That Inhibit the DNA Damage Response Reveals a Novel Histone Binding Protein

Sitz

Shen

et al. 2018

J Virol

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To replicate and persist in human cells, linear double-stranded (ds) DNA viruses, such as Epstein-Barr virus (EBV), must overcome the host DNA damage response (DDR) that is triggered by the viral genomes. Since this response is necessary to maintain cellular genome integrity, its inhibition by EBV is likely an important factor in the development of cancers associated with EBV infection, including gastric carcinoma. Here we present the first extensive screen of EBV proteins that inhibit dsDNA break signaling. We identify the BKRF4 tegument protein as a DDR inhibitor that interferes with histone ubiquitylation at dsDNA breaks and recruitment of the RNF168 histone ubiquitin ligase. We further show that BKRF4 binds directly to histones through an acidic domain that targets BKRF4 to cellular chromatin and is sufficient to inhibit dsDNA break signaling. BKRF4 transcripts were detected in EBV-positive gastric carcinoma cells (AGS-EBV) and these increased in lytic infection. Silencing of BKRF4 in both latent and lytic AGS-EBV cells (but not in EBV-negative AGS cells) resulted in increased dsDNA break signaling, confirming a role for BKRF4 in DDR inhibition in the context of EBV infection and suggesting that BKRF4 is expressed in latent cells. BKRF4 was also found to be consistently expressed in EBV-positive gastric tumours in the absence of a full lytic infection. The results suggest that BKRF4 plays a role in inhibiting the cellular DDR in latent and lytic EBV infection, and that the resulting accumulation of DNA damage might contribute to development of gastric carcinoma. Epstein-Barr virus (EBV) infects most people worldwide and is causatively associated with several types of cancer, including ∼10% of gastric carcinoma. EBV encodes ∼80 proteins many of which are believed to manipulate cellular regulatory pathways but are poorly characterized. The DNA damage response (DDR) is one such pathway that is critical for maintaining genome integrity and preventing cancer-associated mutations. Here a screen for EBV proteins that inhibit the DDR identified BKRF4 as a DDR inhibitor that binds histones and block their ubiquitylation at the DNA damage sites. We also present evidence that BKRF4 is expressed in both latent and lytic forms of EBV infection, where it down-regulates the DDR, as well as in EBV-positive gastric tumours. The results suggest that BKRF4 could contribute to the development of gastric carcinoma through its ability to inhibit the DDR.

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Manipulation of PML Nuclear Bodies and DNA Damage Responses by DNA Viruses

Cited by 3 publications

References 190 publications

Arsenicals, the Integrated Stress Response, and Epstein–Barr Virus Lytic Gene Expression

Arsenicals, the Integrated Stress Response, and Epstein–Barr Virus Lytic Gene Expression

A genome-wide screen of Epstein-Barr virus proteins that modulate host SUMOylation identifies a SUMO E3 ligase conserved in herpesviruses

A Screen for Epstein-Barr Virus Proteins That Inhibit the DNA Damage Response Reveals a Novel Histone Binding Protein

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