scholarly journals Simian virus-40 infection inhibits DNA damage-induced enhancement of CD95 expression and function

Oncogene ◽  
2002 ◽  
Vol 21 (2) ◽  
pp. 190-197 ◽  
Author(s):  
Michael A Sheard ◽  
Borivoj Vojtesek
Keyword(s):  
Dna Damage ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
And Function

scholarly journals Binding of a sequence-specific single-stranded DNA-binding factor to the simian virus 40 core origin inverted repeat domain is cell cycle regulated.

1993 ◽  
Vol 13 (1) ◽  
pp. 408-420 ◽  
Author(s):  
E P Carmichael ◽  
J M Roome ◽  
A F Wahl
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Binding ◽  
Dna Synthesis ◽  
Inverted Repeat ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Single Stranded Dna ◽  
Repeat Domain

The inverted repeat domain (IR domain) within the simian virus 40 origin of replication is the site of initial DNA melting prior to the onset of DNA synthesis. The domain had previously been shown to be bound by a cellular factor in response to DNA damage. We demonstrate that two distinct cellular components bind opposite strands of the IR domain. Replication protein A (RPA), previously identified as a single-stranded DNA binding protein required for origin-specific DNA replication in vitro, is shown to have a preference for the pyrimidine-rich strand. A newly described component, IR factor B (IRF-B), specifically recognizes the opposite strand. IRF-B binding activity in nuclear extract varies significantly with cell proliferation and the cell cycle, so that binding of IRF-B to the IR domain is negatively correlated with the onset of DNA synthesis. Loss of IRF-B binding from the nucleus also occurs in response to cellular DNA damage. UV cross-linking indicates that the core binding component of IRF-B is a protein of ca. 34 kDa. We propose that RPA and IRF-B bind opposite strands of the IR domain and together may function in the regulation of origin activation.

scholarly journals Multiple DNA Damage Signaling and Repair Pathways Deregulated by Simian Virus 40 Large T Antigen

2010 ◽  
Vol 84 (16) ◽  
pp. 8007-8020 ◽  
Author(s):  
Sergei Boichuk ◽  
Liang Hu ◽  
Jennifer Hein ◽  
Ole V. Gjoerup
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Viral Replication ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Productive Infection ◽  
Large T Antigen ◽  
Sv40 Large T Antigen ◽  
Viral Origin

ABSTRACT We demonstrated previously that expression of simian virus 40 (SV40) large T antigen (LT), without a viral origin, is sufficient to induce the hallmarks of a cellular DNA damage response (DDR), such as focal accumulation of γ-H2AX and 53BP1, via Bub1 binding. Here we expand our characterization of LT effects on the DDR. Using comet assays, we demonstrate that LT induces overt DNA damage. The Fanconi anemia pathway, associated with replication stress, becomes activated, since FancD2 accumulates in foci, and monoubiquitinated FancD2 is detected on chromatin. LT also induces a distinct set of foci of the homologous recombination repair protein Rad51 that are colocalized with Nbs1 and PML. The FancD2 and Rad51 foci require neither Bub1 nor retinoblastoma protein binding. Strikingly, wild-type LT is localized on chromatin at, or near, the Rad51/PML foci, but the LT mutant in Bub1 binding is not localized there. SV40 infection was previously shown to trigger ATM activation, which facilitates viral replication. We demonstrate that productive infection also triggers ATR-dependent Chk1 activation and that Rad51 and FancD2 colocalize with LT in viral replication centers. Using small interfering RNA (siRNA)-mediated knockdown, we demonstrate that Rad51 and, to a lesser extent, FancD2 are required for efficient viral replication in vivo, suggesting that homologous recombination is important for high-level extrachromosomal replication. Taken together, the interplay of LT with the DDR is more complex than anticipated, with individual domains of LT being connected to different subcomponents of the DDR and repair machinery.

scholarly journals Atm Is Dispensable for p53 Apoptosis and Tumor Suppression Triggered by Cell Cycle Dysfunction

1999 ◽  
Vol 19 (4) ◽  
pp. 3095-3102 ◽  
Author(s):  
Mai-Jing Liao ◽  
Chaoying Yin ◽  
Carrolee Barlow ◽  
Anthony Wynshaw-Boris ◽  
Terry van Dyke
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Tumor Suppression ◽  
Cancer Susceptibility ◽  
Tumor Model ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Checkpoint Pathway ◽  
Brain Tumor Model

ABSTRACT Both p53 and ATM are checkpoint regulators with roles in genetic stabilization and cancer susceptibility. ATM appears to function in the same DNA damage checkpoint pathway as p53. However, ATM’s role in p53-dependent apoptosis and tumor suppression in response to cell cycle dysregulation is unknown. In this study, we tested the role of murine ataxia telangiectasia protein (Atm) in a transgenic mouse brain tumor model in which p53-mediated apoptosis results in tumor suppression. These p53-mediated activities are induced by tissue-specific inactivation of pRb family proteins by a truncated simian virus 40 large T antigen in brain epithelium. We show that p53-dependent apoptosis, transactivation, and tumor suppression are unaffected by Atm deficiency, suggesting that signaling in the DNA damage pathway is distinct from that in the oncogene-induced pathway. In addition, we show that Atm deficiency has no overall effect on tumor growth and progression in this model.

scholarly journals Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding

2008 ◽  
Vol 83 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Jennifer Hein ◽  
Sergei Boichuk ◽  
Jiaping Wu ◽  
Yuan Cheng ◽  
Raimundo Freire ◽  
...  
Keyword(s):  
Dna Damage ◽  
Viral Replication ◽  
Dna Damage Response ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Genome Integrity ◽  
Large T Antigen ◽  
Sv40 Large T Antigen ◽  
Damage Response

ABSTRACT Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that is important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shown to lead to the induction of DNA damage response signaling, which is required for efficient viral replication. However, it was not clear if LT is sufficient to induce the damage response and, if so, what the genetic requirements and functional consequences might be. Here, we show that the expression of LT alone, without a replication origin, can induce key DNA damage response markers including the accumulation of γ-H2AX and 53BP1 in nuclear foci. Other DNA damage-signaling components downstream of ATM/ATR kinases were induced, including chk1 and chk2. LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins. Stimulation of the damage response by LT depends mainly on binding to Bub1 rather than to the retinoblastoma protein. LT has long been known to stabilize p53 despite functionally inactivating it. We show that the activation of a DNA damage response by LT via Bub1 appears to play a major role in p53 stabilization by promoting the phosphorylation of p53 at Ser15. Accompanying the DNA damage response, LT induces tetraploidy, which is also dependent on Bub1 binding. Taken together, our data suggest that LT, via Bub1 binding, breaches genome integrity mechanisms, leading to DNA damage responses, p53 stabilization, and tetraploidy.

scholarly journals Caspase-2 activation in the absence of PIDDosome formation

2009 ◽  
Vol 185 (2) ◽  
pp. 291-303 ◽  
Author(s):  
Claudia Manzl ◽  
Gerhard Krumschnabel ◽  
Florian Bock ◽  
Benedicte Sohm ◽  
Verena Labi ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Dna Damage ◽  
High Molecular Weight ◽  
Nuclear Translocation ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Death Domain ◽  
High Molecular Weight Complex ◽  
Effector Caspase ◽  
Caspase 2

PIDD (p53-induced protein with a death domain [DD]), together with the bipartite adapter protein RAIDD (receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a DD), is implicated in the activation of pro–caspase-2 in a high molecular weight complex called the PIDDosome during apoptosis induction after DNA damage. To investigate the role of PIDD in cell death initiation, we generated PIDD-deficient mice. Processing of caspase-2 is readily detected in the absence of PIDDosome formation in primary lymphocytes. Although caspase-2 processing is delayed in simian virus 40–immortalized pidd−/− mouse embryonic fibroblasts, it still depends on loss of mitochondrial integrity and effector caspase activation. Consistently, apoptosis occurs normally in all cell types analyzed, suggesting alternative biological roles for caspase-2 after DNA damage. Because loss of either PIDD or its adapter molecule RAIDD did not affect subcellular localization, nuclear translocation, or caspase-2 activation in high molecular weight complexes, we suggest that at least one alternative PIDDosome-independent mechanism of caspase-2 activation exists in mammals in response to DNA damage.

scholarly journals In vitro analysis of UV-damage-induced inhibition of replication

1998 ◽  
Vol 330 (1) ◽  
pp. 181-187 ◽  
Author(s):  
Rachid DRISSI ◽  
Suk-Hee LEE
Keyword(s):  
Dna Damage ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Replication Proteins ◽  
Protein Factor ◽  
Cell Extracts ◽  
Sv40 Origin ◽  
Replication Activity ◽  
Damaged Dna

We investigated DNA-damage-induced inhibition of replication by using an in vitro system, with which both replication and repair can be examined simultaneously. The system contains non-irradiated simian virus 40 (SV40) origin-containing DNA, UV-irradiated circular duplex DNA lacking an SV40 origin, and cell extracts that support both replication and repair activities. Using this system, we show that replication is significantly inhibited in the presence of UV-irradiated, but not non-irradiated, DNA and, to a lesser extent, repair activity is also inhibited by the presence of replication activity. In contrast, replication activity was not affected by UV-damaged DNA when the reactions were carried out with purified replication proteins, suggesting that protein factor(s) in the cell extracts are involved in the inhibition of replication that is triggered by DNA damage. Inhibition was efficiently reversed by the combined actions of proteins involved in both repair and replication, suggesting that the inhibition of replication observed in our system may be caused by the recruitment of replication proteins to damaged DNA sites.

scholarly journals Recombination induced by triple-helix-targeted DNA damage in mammalian cells.

1996 ◽  
Vol 16 (12) ◽  
pp. 6820-6828 ◽  
Author(s):  
A F Faruqi ◽  
M M Seidman ◽  
D J Segal ◽  
D Carroll ◽  
P M Glazer
Keyword(s):  
Gene Therapy ◽  
Dna Damage ◽  
Gene Conversion ◽  
Mammalian Cells ◽  
Triple Helix ◽  
Low Frequency ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Or Gene ◽  
New Research

Gene therapy has been hindered by the low frequency of homologous recombination in mammalian cells. To stimulate recombination, we investigated the use of triple-helix-forming oligonucleotides (TFOs) to target DNA damage to a selected site within cells. By treating cells with TFOs linked to psoralen, recombination was induced within a simian virus 40 vector carrying two mutant copies of the supF tRNA reporter gene. Gene conversion events, as well as mutations at the target site, were also observed. The variety of products suggests that multiple cellular pathways can act on the targeted damage, and data showing that the triple helix can influence these pathways are presented. The ability to specifically induce recombination or gene conversion within mammalian cells by using TFOs may provide a new research tool and may eventually lead to novel applications in gene therapy.

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