p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress

Marusyk, Andriy; Wheeler, Linda J.; Mathews, Christopher K.; DeGregori, James

doi:10.1128/mcb.01316-06

Cited by 63 publications

(67 citation statements)

References 88 publications

(106 reference statements)

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“…Appearance of these foci may be a result of replication-associated DNA damage that the cell is attempting to repair by HR. In the absence of functional p53, Rad51 was previously found upregulated (38,75). Indeed, p53 can also suppress HR by direct binding to Rad51 (36).…”

Section: Discussionmentioning

confidence: 94%

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

Boichuk

Hein

et al. 2010

J Virol

107

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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: 94%

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

Boichuk

Hein

et al. 2010

J Virol

107

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“…Next, we examined whether other senescence-evoking compounds such as aphidicolin (APH 43 ), thymidine (TMD 44 ), etoposide (ET 45 ) and camptothecin (CPT [46][47][48] ) are able to induce in BJ cells (Fig. 2C), which corresponded to faster onset of senescence in these settings (data not shown).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the PML tumor suppressor in drug-induced senescence of human normal and cancer cells by JAK/STAT-mediated signaling

Hubáčková¹,

Nováková²,

Krejčíková³

et al. 2010

Cell Cycle

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the promyelocytic leukemia protein (pML) tumor suppressor is upregulated in several forms of cellular senescence, however the mechanism of its induction is elusive. Here we show that genotoxic drugs that induce senescence, such as 5-bromo-2'deoxyuridine (BrdU), thymidine (tMD), distamycin A (DMA), aphidicolin (ApH), etoposide (et) and camptothecin (Cpt) all evoke expansion of pML nuclear compartment and its association with persistent DNA lesions in several human cancer cell lines and normal diploid fibroblasts. this phenomenon was accompanied by elevation of pML transcripts after treatment with BrdU, tMD, DMA and Cpt. Chemical inhibition of all JAK kinases and RNAi-mediated knock-down of JAK1 suppressed pML expression, implicating JAK/StAt-mediated signaling in regulation of the pML gene. As pML protein stability remained unchanged after drug treatment, decreased protein turnover was unlikely to explain the senescence-associated increased abundance of pML. Furthermore, binding activity of Interferon Stimulated Response element (ISRe) within the pML gene promoter, and suppression of reporter gene activity after deletion of ISRe from the pML promoter region suggested that drug-induced pML transcription is controlled via transcription factors interacting with this element. Collectively, our data show that upregulation of the pML tumor suppressor in cellular senescence triggered by diverse drugs including clinically used anti-cancer chemotherapeutics relies on stimulation of pML transcription by JAK/StAt-mediated signaling, possibly evoked by the autocrine/paracrine activities of senescenceassociated cytokines.

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“…Primary MEF immortalization assays were performed as previously described (8). For detection of the phenotype with an abnormal p53 pathway, each population was cultured in medium containing hydroxyurea (HU) as previously described (25). Sphere formation assay was performed as previously described (26) with a little modification.…”

Section: Methodsmentioning

confidence: 99%

“…2C). Next, to determine the status of functional loss of the Arf/p53 pathway, p53-mediated senescence-like arrest was investigated using treatment with a low dose of HU, which induces DNA replication stress but allows continuous proliferation in p53-mutated populations (25). Although the cGCs in FBS-med as well as primary MEFs were completely arrested by HU treatment (supplemental Fig.…”

Section: Escs Differentiating In An Aberrant Environment Senesce Aftementioning

confidence: 99%

Induction of Cancerous Stem Cells during Embryonic Stem Cell Differentiation

Fujimori

Shikanai

Teraoka

et al. 2012

Journal of Biological Chemistry

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Background: Cancer stem cells are responsible for tumorigenesis; however, the developmental process is poorly understood. Results: Differentiating stem cells in aberrant environments are subjected to carcinogenic stress, leading to genomic instabilization, mutation inductions, and cellular transformation with stemness characteristics. Conclusion: Aberrant environment for differentiation risks cancerous stem cell development. Significance: This is the first report showing normal stem cell transformation into malignant counterparts and their process.

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p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress

Cited by 63 publications

References 88 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

Regulation of the PML tumor suppressor in drug-induced senescence of human normal and cancer cells by JAK/STAT-mediated signaling

Induction of Cancerous Stem Cells during Embryonic Stem Cell Differentiation

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