p53 accumulates but is functionally impaired when DNA synthesis is blocked

Gottifredi, Vanesa; Shieh, Sheau‐Yann; Taya, Yoichi; Prives, Carol

doi:10.1073/pnas.98.3.1036

Cited by 154 publications

(167 citation statements)

References 54 publications

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“…p53 was shown to respond to the replication block induced by aphidicolin (Gottifredi et al, 2001;Nayak and Das, 2002) and colocalized with BLM, Rad51 and 53BP1 at the sites of stalled DNA replication fork (Sengupta et al, 2003(Sengupta et al, , 2004. p53 also accumulated during S-phase in Cdc7À/À ES cells with defective replication origin firing (Kim et al, 2002).…”

Section: Introductionmentioning

confidence: 96%

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

et al. 2006

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The S-phase DNA damage checkpoint is activated by DNA damage to delay DNA synthesis allowing time to resolve the replication block. We previously discovered the p53-dependent S-phase DNA damage checkpoint in mouse zygotes fertilized with irradiated sperm. Here, we report that the same p53 dependency holds in mouse embryonic fibroblasts (MEFs) at low doses of irradiation. DNA synthesis in p53 wild-type (WT) MEFs was suppressed in a biphasic manner in which a sharp decrease below 2.5 Gy was followed by a more moderate decrease up to 10 Gy. In contrast, p53À/À MEFs exhibited radioresistant DNA synthesis below 2.5 Gy whereas the cells retained the moderate suppression above 5 Gy. DNA fiber analysis revealed that 1 Gy irradiation suppressed replication fork progression in p53 WT MEFs, but not in p53À/À MEFs. Proliferating cell nuclear antigen (PCNA), clamp loader of DNA polymerase, was phosphorylated in WT MEFs after 1 Gy irradiation and redistributed to form foci in the nuclei. In contrast, PCNA was not phosphorylated and dissociated from chromatin in 1 Gy-irradiated p53À/À MEFs. These results demonstrate that the novel low-dosespecific p53-dependent S-phase DNA damage checkpoint is likely to regulate the replication fork movement through phosphorylation of PCNA.

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Section: Introductionmentioning

confidence: 96%

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

et al. 2006

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“…Remarkably, p53 does not transcriptionally transactivate target genes in cells, which were synchronized in S phase by treatment with a replication elongation inhibitor (Gottifredi et al, 2001). To the contrary, p53 is active in regulating recombinative repair under these conditions (Saintigny and Lopez, 2002;this work).…”

Section: Indications For An Antagonistic Role Of P53 During Replicatimentioning

confidence: 99%

Wild-type p53 inhibits replication-associated homologous recombination

Janz

Wiesmüller

2002

Oncogene

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In mammalian cells homologous recombination is stimulated, when the replication fork stalls at DNA breaks or unrepaired lesions. The tumor suppressor p53 downregulates homologous recombination independently of its transcriptional transactivation function and has been linked to enzymes of DNA recombination and replication. To study recombination with respect to replication, we utilized a SV40 virus based assay, to follow the synchronous events after primate cell infection. g-ray treatment at different times after viral entry unveiled an increase of interchromosomal exchange frequencies, when the damage was introduced during DNA synthesis. Elevated recombination frequencies were fully suppressed by p53. With respect to the downregulation of spontaneous recombination, we noticed a requirement for active p53 molecules, when replication started. After a transient treatment with replication inhibitors, we observed inhibition of the drug induced recombination by p53, particularly for the elongation inhibitor aphidicolin. Consequently, we propose that p53 is a surveillance factor of homologous recombination at replication forks, when they stall as a consequence of endogenous or of exogenously introduced damage.

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“…In another role, ATR may also be involved in signaling for apoptosis. ATR can directly or indirectly, through Chk1 kinase, activate p53 by phosphorylation (Tibbetts et al, 1999;Shieh et al, 2000), leading to protein stabilization and transcriptional attenuation (Gottifredi et al, 2001).…”

Section: Molecular Sensing Of Dna Damagementioning

confidence: 99%

Nucleoside analogs: molecular mechanisms signaling cell death

2008

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Nucleoside analogs are structurally similar antimetabolites that have a broad range of action and are clinically active in both solid tumors and hematological malignancies. Many of these agents are incorporated into DNA by polymerases during normal DNA synthesis, an action that blocks further extension of the nascent strand and causes stalling of replication forks. The molecular mechanisms that sense stalled replication forks activate cell cycle checkpoints and DNA repair processes, which may contribute to drug resistance. When replication forks are not stabilized by these molecules or when subsequent DNA repair processes are overwhelmed, apoptosis is initiated either by these same DNA damage sensors or by alternative mechanisms. Recently, strategies aimed at targeting DNA damage checkpoints or DNA repair processes have demonstrated effectiveness in sensitizing cells to nucleoside analogs, thus offering a means to elude drug resistance. In addition to their DNA synthesisdirected actions many nucleoside analogs trigger apoptosis by unique mechanisms, such as causing epigenetic modifications or by direct activation of the apoptosome. A review of the cellular and molecular responses to clinically relevant agents provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies.

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p53 accumulates but is functionally impaired when DNA synthesis is blocked

Cited by 154 publications

References 54 publications

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

Wild-type p53 inhibits replication-associated homologous recombination

Nucleoside analogs: molecular mechanisms signaling cell death

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