Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

Willers, Henning; McCarthy, Ellen E.; Wu, Biao; Wunsch, Hannah; Tang, Wei; Taghian, Danielle G.; Xia, Fang; Powell, Simon N.

doi:10.1038/sj.onc.1203142

Cited by 103 publications

(110 citation statements)

References 50 publications

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“…This strongly indicates a direct rather than a transcriptiondependent action of p53 during recombination. This is in line with earlier reports on the separation of transcriptional, growth regulatory and apoptotic activities of p53 from recombination regulation (Saintigny et al, 1999;Dudenho¨ffer et al, 1999;Willers et al, 2000;Akyu¨z et al, 2002). Data from in vivo models for transcriptionally inactive p53 indicated the existence of an unidentified activity counteracting cancerogenesis (Komarov et al, 1999;Jimenez et al, 2000).…”

Section: Indications For An Antagonistic Role Of P53 During Replicatisupporting

confidence: 80%

“…Wild-type p53 (wtp53) stabilizes the genome by G1 arrest and pro-apoptotic functions, thereby giving time to repair and eliminate cells with irrepairable damage, respectively (Levine, 1997). During the last years it was also established that p53 downregulates homologous recombination independently of its transcriptional transactivation and growth regulatory functions (Saintigny et al, 1999;Dudenho¨ffer et al, 1999;Willers et al, 2000). This activity is directed towards gene conversion events, involving short stretches of homologies in particular (Bertrand et al, 1997;Saintigny et al, 1999;Akyu¨z et al, 2002).…”

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confidence: 99%

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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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Section: Indications For An Antagonistic Role Of P53 During Replicatisupporting

confidence: 80%

mentioning

confidence: 99%

Wild-type p53 inhibits replication-associated homologous recombination

Janz

Wiesmüller

2002

Oncogene

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“…Intriguingly, p53 protein appears to promote only some DNA damage repair pathways, such as base excision repair, mismatch repair and nucleotide excision repair [9][10][11], but inhibit DNA DSB repair pathways, including the HR, NHEJ and SSA pathways [12][13][14]. It has been demonstrated that p53 exerts a direct effect on DNA DSB repair, as mutations in p53 that impair or even abolish its transcriptional activity and cell cycle regulatory capacity do not significantly affect its inhibition of HR [15][16][17]. Further experiments have shown that the p53 protein is able to interact with repair proteins to prevent repair complex formation, such as RAD51 (a recombinase for HR) and replication protein A (RPA; a single-strand DNA-interacting protein required for stabilizing processed DNA ends) [16,18,19].…”

Section: Introductionmentioning

confidence: 99%

p53 isoform Δ113p53/Δ133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage

Gong¹,

Gong²,

Pan³

et al. 2015

Cell Res

134

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The inhibitory role of p53 in DNA double-strand break (DSB) repair seems contradictory to its tumor-suppressing property. The p53 isoform ∆113p53/∆133p53 is a p53 target gene that antagonizes p53 apoptotic activity. However, information on its functions in DNA damage repair is lacking. Here we report that ∆113p53 expression is strongly induced by γ-irradiation, but not by UV-irradiation or heat shock treatment. Strikingly, ∆113p53 promotes DNA DSB repair pathways, including homologous recombination, non-homologous end joining and single-strand annealing. To study the biological significance of ∆113p53 in promoting DNA DSB repair, we generated a zebrafish ∆113p53 M/M mutant via the transcription activator-like effector nuclease technique and found that the mutant is more sensitive to γ-irradiation. The human ortholog, ∆133p53, is also only induced by γ-irradiation and functions to promote DNA DSB repair. ∆133p53-knockdown cells were arrested at the G2 phase at the later stage in response to γ-irradiation due to a high level of unrepaired DNA DSBs, which finally led to cell senescence. Furthermore, ∆113p53/∆133p53 promotes DNA DSB repair via upregulating the transcription of repair genes rad51, lig4 and rad52 by binding to a novel type of p53-responsive element in their promoters. Our results demonstrate that ∆113p53/∆133p53 is an evolutionally conserved pro-survival factor for DNA damage stress by preventing apoptosis and promoting DNA DSB repair to inhibit cell senescence. Our data also suggest that the induction of ∆133p53 expression in normal cells or tissues provides an important tolerance marker for cancer patients to radiotherapy.

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“…Many studies have indicated p53 being an important integral part of these checkpoints (Bargonetti and Manfredi, 2002). Accumulated p53 in response to DNA damage or through experimental overexpression has been shown to cause growth arrest at G1 (Agami and Bernards, 2000;Wesierska-Gadek and Schmid, 2000;Willers et al, 2000) and/or G2 (Agarwal et al, 1995;Taylor et al, 1999;Taylor and Stark, 2001;Nakamura et al, 2002) or to induce apoptosis (Vousden, 2000;Kokontis et al, 2001). In some cases, overexpression of the wt p53 induces cellular senescence (Sugrue et al, 1997;Dubrez et al, 2001;Jung et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Identification of PRC1 as the p53 target gene uncovers a novel function of p53 in the regulation of cytokinesis

Lin

2004

Oncogene

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Our previous studies conducted in MCF7-ptsp53 cells have demonstrated that overexpression of the wild-type (wt) p53 at permissive temperature 321C leads to growth arrest at the G2/M phase of the cell cycle. To identify novel p53-regulated genes that are responsible for the p53-induced G2/M arrest, we conducted cDNA microarray analyses. The array results indicated that the mRNA level of protein regulator of cytokinesis (PRC1) was significantly decreased when the p53 transactivation activity was turned on, suggesting that PRC1 transcription could be downregulated by p53. In this study, we have extensively examined the functional role of p53 in the regulation of PRC1, a cell cycle protein that plays important roles during cytokinesis. We demonstrate that increased expression of the wt p53 either by exogenous transfection or chemical induction results in reduced mRNA and protein expression of PRC1 in HCT116 p53 þ / þ , HCT116 p53 À/À , MCF-7, T47D, and HeLa cells. Importantly, we show that the decreased PRC1 expression is accompanied by the appearance of binucleated cells, indicating the process of cell division after mitosis being inhibited. By isolation and characterization of a 3 kb genomic fragment containing the 5 0 -flanking region and part of exon 1 of PRC1 gene, we demonstrate that p53 directly suppresses PRC1 gene transcription. We further locate the p53-responsive sequence to the proximal promoter region À214 to -163, relative to the transcriptional start site. The in vivo interaction of p53 with PRC1 gene promoter is further demonstrated by chromatin immunoprecipitation assay. Taken together, these new findings suggest that p53 may have important roles in the regulation of cytokinesis through controlling the transcription of PRC1.

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Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

Cited by 103 publications

References 50 publications

Wild-type p53 inhibits replication-associated homologous recombination

Wild-type p53 inhibits replication-associated homologous recombination

p53 isoform Δ113p53/Δ133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage

Identification of PRC1 as the p53 target gene uncovers a novel function of p53 in the regulation of cytokinesis

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