The cellular Mre11 protein interferes with adenovirus E4 mutant DNA replication

Mathew, Shomita S.; Bridge, Eileen

doi:10.1016/j.virol.2007.03.049

Cited by 41 publications

(77 citation statements)

References 35 publications

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“…The proteins of the MRN complex recognize double-strand breaks in DNA to activate signaling pathways that result in repair by recombination or nonhomologous end joining (NHEJ) (14)(15)(16)(17). It is well established that when MRN components are not targeted for degradation by the virus-specific E3 Ub ligase or relocalized by the viral E4 Orf3 protein (8,18), viral DNA synthesis is impaired in infected cells (19)(20)(21). Furthermore, late in the infectious cycle, concatemers of randomly oriented copies of the viral genome are formed in NHEJ-dependent reactions (8,22,23).…”

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confidence: 99%

The Repression Domain of the E1B 55-Kilodalton Protein Participates in Countering Interferon-Induced Inhibition of Adenovirus Replication

Chahal

Gallagher

DeHart

et al. 2013

J Virol

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]), we examined the effects of precise amino acid substitution in this protein on resistance of viral replication to the cytokine. Only substitution of residues 443 to 448 of E1B for alanine (E1B Sub19) specifically impaired production of progeny virus and resulted in a large defect in viral DNA synthesis in IFN-treated normal human fibroblasts. Untreated or IFN-treated cells infected by this mutant virus (AdEasyE1Sub19) contained much higher steady-state concentrations of IFN-inducible GBP1 and IFIT2 mRNAs than did wild-typeinfected cells and of the corresponding newly transcribed pre-mRNAs, isolated exploiting 5=-ethynyluridine labeling and click chemistry. These results indicated that the mutations created by substitution of residues 443 to 448 for alanine (Sub19) impair repression of transcription of IFN-inducible genes, by the E1B, 55-kDa protein, consistent with their location in a segment required for repression of p53-dependent transcription. However, when synthesized alone, the E1B 55-kDa protein inhibited expression of the p53-regulated genes BAX and MDM2 but had no impact whatsoever on induction of IFIT2 and GBP1 expression by IFN. These observations correlate repression of transcription of IFN-inducible genes by the E1B 55-kDa protein with protection against inhibition of viral genome replication and indicate that the E1B 55-kDa protein is not sufficient to establish such transcriptional repression.T he E1B gene of species C human adenoviruses such as adenovirus type 5 (Ad5) encodes major, unrelated proteins of 19 and 55 kDa, each of which can cooperate with viral E1A gene products to transform rodent cells and counter host cell responses detrimental to viral replication (1, 2). The E1B 19-kDa protein is a viral homolog of cellular antiapoptotic proteins such as Bcl2 and blocks induction of apoptosis by the E1A proteins in transformed and infected cells (2, 3). The known protective functions of the E1B 55-kDa protein are fulfilled by a virus-specific E3 ubiquitin (Ub) ligase assembled from the E1B and the viral E4 Orf6 proteins and the cellular proteins cullin5, elongins B and C, and Rbx1 (4, 5), which ubiquitinylates multiple cellular substrates to target them for subsequent proteasomal degradation. These substrates include the cellular tumor suppressor p53 (4-7) and the Mre11, Rad50, and Nbs1 proteins, which comprise the MRN complex (8). As the viral immediate-early E1A 243R protein can induce apoptosis via stabilization of p53 (9-12), removal of the latter protein as a result of the action of the E1B 55-kDa protein-containing E3 Ub ligase is thought to prevent induction of G 1 arrest or apoptosis in infected cells (1, 2, 13). The proteins of the MRN complex recognize double-strand breaks in DNA to activate signaling pathways that result in repair by recombination or nonhomologous end joining (NHEJ) (14-17). It is well established that when MRN components are not targeted for degradation by the virus-specific E3 Ub ligase or relocalized by the viral E4 Orf3 protein (8, 18), viral DNA synthesis is i...

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confidence: 99%

The Repression Domain of the E1B 55-Kilodalton Protein Participates in Countering Interferon-Induced Inhibition of Adenovirus Replication

Chahal

Gallagher

DeHart

et al. 2013

J Virol

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“…The Ad5 E4-ORF3 protein relocalizes nuclear proteins involved in a DDR, including Mre11, Rad50, and Nbs1 (the MRN complex) into the track structures (17,18). The available evidence suggests that E4-ORF3 inhibits the functions of these DNA repair proteins by a sequestration mechanism to block their access to the viral genome (17)(18)(19)(20)(21). The Ad5 E1B-55K⅐E4-ORF6 complex functions as an adaptor molecule in an E3 ubiquitin ligase complex (22,23).…”

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confidence: 99%

Biophysical and Functional Analyses Suggest That Adenovirus E4-ORF3 Protein Requires Higher-order Multimerization to Function against Promyelocytic Leukemia Protein Nuclear Bodies

Patsalo

Yondola

Luan

et al. 2012

Journal of Biological Chemistry

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Background:The adenovirus E4-ORF3 protein disrupts PML nuclear bodies to inhibit antiviral activity. Results: The WT E4-ORF3 protein forms higher-order multimers, whereas a nonfunctional mutant forms a dimer. Conclusion: E4-ORF3 protein multimerization likely is required for the activity of this protein.Significance: These results provide new insight into the properties of the adenovirus E4-ORF3 protein and suggest that higher-order protein multimerization is essential for activity.

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“…We have previously observed that the MRN sensor complex is needed for efficient Mdc1 focus formation in Ad-infected cells (31) and that both Mre11 and Mdc1 are bound to viral DNA at early times after infection in chromatin immunoprecipitation (ChIP) experiments (32). Mdc1 focus formation is correlated with MOI ( Fig.…”

Section: Discussionmentioning

confidence: 96%

“…We have previously found that Mdc1 focus formation can be observed by 4 hpi before the onset of viral DNA replication in both Ad5 and E4 mutant infections (31). AdRSV␤gal lacks E1 and is therefore deficient for both viral early gene expression and DNA replication (5).…”

Section: Mdc1 Focus Formation Is Correlated With the Moi And Requiresmentioning

confidence: 99%

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Differential Activation of Cellular DNA Damage Responses by Replication-Defective and Replication-Competent Adenovirus Mutants

Prakash

Jayaram

Bridge

2012

J Virol

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Adenovirus (Ad) mutants that lack early region 4 (E4) activate the phosphorylation of cellular DNA damage response proteins. In wild-type Ad type 5 (Ad5) infections, E1b and E4 proteins target the cellular DNA repair protein Mre11 for redistribution and degradation, thereby interfering with its ability to activate phosphorylation cascades important during DNA repair. The characteristics of Ad infection that activate cellular DNA repair processes are not yet well understood. We investigated the activation of DNA damage responses by a replication-defective Ad vector (AdRSVβgal) that lacks E1 and fails to produce the immediate-early E1a protein. E1a is important for activating early gene expression from the other viral early transcription units, including E4. AdRSVβgal can deliver its genome to the cell, but it is subsequently deficient for viral early gene expression and DNA replication. We studied the ability of AdRSVβgal-infected cells to induce cellular DNA damage responses. AdRSVβgal infection does activate formation of foci containing the Mdc1 protein. However, AdRSVβgal fails to activate phosphorylation of the damage response proteins Nbs1 and Chk1. We found that viral DNA replication is important for Nbs1 phosphorylation, suggesting that this step in the viral life cycle may provide an important trigger for activating at least some DNA repair proteins.

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The cellular Mre11 protein interferes with adenovirus E4 mutant DNA replication

Cited by 41 publications

References 35 publications

The Repression Domain of the E1B 55-Kilodalton Protein Participates in Countering Interferon-Induced Inhibition of Adenovirus Replication

The Repression Domain of the E1B 55-Kilodalton Protein Participates in Countering Interferon-Induced Inhibition of Adenovirus Replication

Biophysical and Functional Analyses Suggest That Adenovirus E4-ORF3 Protein Requires Higher-order Multimerization to Function against Promyelocytic Leukemia Protein Nuclear Bodies

Differential Activation of Cellular DNA Damage Responses by Replication-Defective and Replication-Competent Adenovirus Mutants

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