Evidence for a Structural Relationship between BRCT Domains and the Helicase Domains of the Replication Initiators Encoded by the<i>Polyomaviridae</i>and<i>Papillomaviridae</i>Families of DNA Tumor Viruses

Kumar, Anuradha; Joo, Woo S.; Meinke, Gretchen; Moine, Stephanie; Naumova, Elena N.; Bullock, Peter A.

doi:10.1128/jvi.00553-08

Cited by 3 publications

(3 citation statements)

References 111 publications

(117 reference statements)

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“…Indeed, we know that specific ATM inhibition causes at least partial loss of LT localization at replication centers (76). The BRCT-related region present within the SV40 helicase domain suggests another potential mode of recruitment (31). BRCT domains, present in Mdc1 and BRCA1, are phosphoserine/threonine-dependent interaction modules important for DDR signaling (43).…”

Section: Discussionmentioning

confidence: 99%

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

Boichuk

Hein

et al. 2010

J Virol

112

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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 ␥-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.Simian virus 40 (SV40) carries genes encoding three early proteins: large T antigen (LT), small t antigen, and 17k. LT has served as a powerful model system for understanding cellular processes, such as DNA replication and malignant transformation (1, 16). An in vitro SV40 replication system based on purified cellular factors was established long ago, which in many ways recapitulates in vivo replication (33, 71). However, although very insightful, certain aspects of DNA replication cannot be reconstructed in a test tube and remain incompletely understood. Since SV40 relies extensively on cellular replication factors, it must reprogram the cellular environment to support viral DNA replication. A key component is cell cycle reprogramming, perhaps most importantly the potent induction of S phase in quiescent cells (19).The ability of LT to induce aberrant cellular proliferation depends on binding to and inactivating key tumor suppressors like p53 and the retinoblastoma protein (pRB) family (reviewed in references 1 and 16). These interactions are also critical for oncogenic transformation and induction of tumors in a wide variety of cell types and tissues. Additional functions contribute to transformation. A functional DnaJ domain resides within the first 70 amino acids, which directs binding of the Hsc70 molecular chaperone and contributes to both oncogenic transformation and viral replication proficiency (10, ...

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Section: Discussionmentioning

confidence: 99%

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

Boichuk

Hein

et al. 2010

J Virol

112

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“…Despite their conservation in structure and composition, it is obvious that their scaffolding properties are utilized in a diverse fashion within the BRCT family. It is also important to note that BRCT domains have also been identified in plants (47) and a BRCT-related fold has been observed in the T antigen helicase domain of polyoma viruses (48). …”

Section: Evolution Of Brct Domainsmentioning

confidence: 99%

“…It is also important to note that BRCT domains have also been identified in plants 47 and a BRCT-related fold has been observed in the T antigen helicase domain of polyoma viruses. 48…”

Section: Evolution Of Brct Domainsmentioning

confidence: 99%

Tandem BRCT Domains: DNA's Praetorian Guard

et al. 2010

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The cell’s ability to sense and respond to specific stimuli is a complex system derived from precisely regulated protein-protein interactions. Some of these protein-protein interactions are mediated by the recognition of linear peptide motifs by protein modular domains. BRCT (BRCA1 C-terminal) domains and their linear motif counterparts, which contain phosphoserines, are one such pair-wise interaction system that seems to have evolved to serve as a surveillance system to monitor threats to the cell’s genetic integrity. Evidence indicates that BRCT domains found in tandem can cooperate to provide sequence specific binding of phosphorylated peptides as is the case for the breast and ovarian cancer susceptibility gene BRCA1 and the PAX transcription factor interacting protein PAXIP1. Particular interest has been paid to tandem BRCT domains as ‘readers’ of signaling events in the form of phosphorylated serine moieties induced by the activation of DNA damage response kinases ATM, ATR and DNA-PK. However, given the diversity of tandem BRCT containing proteins questions remain as to the origin and evolution of this domain. Here we discuss emerging views of the origin and evolving roles of tandem BRCT domain repeats in the DNA damage response.

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False-positive TUNEL staining observed in SV40 based transgenic murine prostate cancer models

et al. 2013

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The TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) and LADY (Probasin-large T antigen transgenic mouse) mice are widely used autochthonous models of prostate cancer. Both models utilise probasin promoters to direct androgen-regulated expression of oncogenic SV40 specifically to epithelial cells of the mouse prostate. The oncogenic processes and phenotypes which result mimic many features of human prostate cancer, making these transgenic mouse models useful experimental systems. The terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP in situ nick end labelling (TUNEL) assay is a commonly used method for the detection of cells undergoing apoptosis. In this study, we demonstrate false-positive TUNEL staining in frozen prostate tissue from TRAMP and LADY mice, which was not observed in non-transgenic control animals and is not due to non-specific binding of labelled-dUTP substrate. The false-positive signal co-localised with large SV40 T-antigen expression. False-positive signal was apparent using multiple commercial TUNEL kits with different detection systems. These results caution against the use of the TUNEL assay for detection of apoptosis in frozen prostate tissue of large T-antigen based autochthonous transgenic models of prostate cancer.

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Evidence for a Structural Relationship between BRCT Domains and the Helicase Domains of the Replication Initiators Encoded by thePolyomaviridaeandPapillomaviridaeFamilies of DNA Tumor Viruses

Cited by 3 publications

References 111 publications

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

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

Tandem BRCT Domains: DNA's Praetorian Guard

False-positive TUNEL staining observed in SV40 based transgenic murine prostate cancer models

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