Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rad51 protein plays a pivotal role in homologous recombination (HR), which is involved in double-strand break repair and in genome maintenance. Despite interactions with tumor suppressor proteins, the role of mammalian Rad51 and more generally of HR in tumor prevention is not clearly established. Indeed, both high and low frequencies of HR as well as high and low levels of RAD51 expression have been reported in tumors and in precancerous conditions. To address the question of the impact of HR on tumorigenesis, we used Chinese hamster ovary (CHO) p53-defective cell lines overexpressing the mouse MmRAD51, which stimulates HR (we name these lines: Hyper-rec lines). In parallel, we used CHO cell lines expressing a RAD51 dominant-negative form that specifically inhibits gene conversion without affecting cell viability (Hypo-rec lines). These different lines were injected into nude mice to measure their tumorigenicity. Hypo-rec lines generated a higher frequency of tumors, which also exhibited faster growth, compared to control and Hyper-rec lines. Consistent with tumorigenicity, Hypo-rec cells exhibit spontaneous centrosome duplication defects and aneuploidy. These results are the first direct evidence of involvement of RAD51 in tumor repression.
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PMID:Overexpression of mammalian Rad51 does not stimulate tumorigenesis while a dominant-negative Rad51 affects centrosome fragmentation, ploidy and stimulates tumorigenesis, in p53-defective CHO cells. 1457 20

Promyelocytic leukemia nuclear bodies (PML-NBs) are discrete interchromosomal macromolecular structures. The integrity of this dynamic nuclear subcompartment critically depends on the presence of the name-giving PML protein. Among the permanent or transient residents of PML-NBs are various regulatory proteins, including Sp100, CBP, pRb, HIPK2, RAD51 and p53. PML-NBs are frequently targeted by viral infections, as a number of different RNA and DNA viruses, including herpesviruses, adenoviruses, papovaviruses, papillomaviruses and arenaviruses, cause changes in PML-NBs. Viruses interfere with PML-NB in two ways: 1) some viral proteins can associate with PML-NB proteins and/or lead to the destruction and lysis of this subnuclear compartment, thus aiding viral gene expression and disabling the host's innate immunity; 2) the parental genomes of some nuclear-replicating DNA viruses associate preferentially with PML-NBs, which presumably serves to assist in viral gene expression or replication. Here we feature the different viral strategies leading to the hijacking of PML-NBs and discuss the consequences for the immune response.
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PMID:Viruses as hijackers of PML nuclear bodies. 1462 29

We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs (siRNAs) resulted in increased sensitivity to ionizing radiation and defects in G2/M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.
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PMID:Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. 1463 69

Genetic instability caused by mutations in the p53 gene is generally thought to be due to a loss of the DNA damage response that controls checkpoint functions and apoptosis. Cells with mutant p53 exhibit high levels of homologous recombination (HR). This could be an indirect consequence of the loss of DNA damage response or p53 could have a direct role in HR. Here, we report that p53-/- mouse embryonic fibroblasts (MEFs) exhibit higher levels of the RAD51 protein and increased level of spontaneous RAD51 foci Agents that stall replication forks, for example, hydroxyurea (HU), potently induce HR repair and RAD51 foci. To test if the increase in RAD51 foci in p53-/- MEFs was due to an increased level of damage during replication, we measured the formation of DNA double-strand breaks (DSBs) in p53+/+ and p53-/- MEFs following treatments with HU. We found that HU induced DSBs only in p53-/- MEFs, indicating that p53 is involved in a pathway to protect stalled replication forks from being collapsed into a substrate for HR. Also, p53 is upregulated in response to agents that inhibit DNA replication, which supports our hypothesis. Finally, we observed that the DSBs produced in p53-/- MEFs did not result in a permanent arrest of replication and that they were repaired. Altogether, we suggest that the effect of p53 on HR and RAD51 levels and foci can be explained by the idea that p53 suppresses formation of recombinogenic lesions.
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PMID:p53 protects from replication-associated DNA double-strand breaks in mammalian cells. 1474 4

The human MSH2/6 complex is essential for mismatch recognition during the repair of replication errors. Although mismatch repair components have been implicated in DNA homologous recombination repair, the exact function of hMSH2/6 in this pathway is unclear. Here, we show that the recombinant hMSH2/6 protein complex stimulated the ability of the Bloom's syndrome gene product, BLM, to process Holliday junctions in vitro, an activity that could also be regulated by p53. Consistent with these observations, hMSH6 colocalized with BLM and phospho-ser15-p53 in hydroxyurea-induced RAD51 nuclear foci that may correspond to the sites of presumed stalled DNA replication forks and more likely the resultant DNA double-stranded breaks. In addition, we show that hMSH2 and hMSH6 coimmunoprecipitated with BLM, p53, and RAD51. Both the number of RAD51 foci and the amount of the BLM-p53-RAD51 complex are increased in hMSH2- or hMSH6-deficient cells. These data suggest that hMSH2/6 formed a complex with BLM-p53-RAD51 in response to the damaged DNA forks during double-stranded break repair.
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PMID:The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase. 1506 30

The tumor suppressor protein p53 controls cell cycle checkpoints and apoptosis via the transactivation of several genes. However, data from various laboratories suggest an additional role for p53: transcription-independent suppression of homologous recombination (HR). Genetic and physical interactions among p53, HR proteins (e.g. RAD51 and RAD54) and HR-DNA intermediates show that p53 acts directly on HR during the early and late steps of recombination. Complementary to the MSH2 mismatch-repair system, p53 appears to impair excess HR by controlling the minimal efficiency processing segment and by reversing recombination intermediates. By controlling the balance between the BLM and the RAD51 pathways, this direct role of p53 could maintain genome stability when replication forks are stalled at regions of DNA damage. In this article, we discuss the direct role of p53 on HR and the consequences for genome stability, tumor protection and speciation.
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PMID:p53's double life: transactivation-independent repression of homologous recombination. 1514 76

Strict regulation of DNA replication is essential to ensure proper duplication and segregation of chromosomes during the cell cycle, as its deregulation can lead to genomic instability and cancer. Thus, eukaryotic organisms have evolved multiple mechanisms to restrict DNA replication to once per cell cycle. Here, we show that inactivation of Geminin, an inhibitor of origin licensing, leads to rereplication in human normal and tumor cells within the same cell cycle. We found a CHK1-dependent checkpoint to be activated in rereplicating cells accompanied by formation of gammaH2AX and RAD51 nuclear foci. Abrogation of the checkpoint leads to abortive mitosis and death of rereplicated cells. In addition, we demonstrate that the induction of rereplication is dependent on the replication initiation factors CDT1 and CDC6, and independent of the functional status of p53. These data show that Geminin is required for maintaining genomic stability in human cells.
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PMID:Loss of Geminin induces rereplication in the presence of functional p53. 1515 17

DNA repair genes play a major role in maintaining genomic stability through different repair pathways that are mediated by cell cycle control genes such as p53. We found previously that glioma patients were susceptible to gamma-ray-induced chromosomal breaks, which may be influenced by genetic variation in genes involved in DNA strand breaks, such as XRCC1 in single-strand break repair, XRCC3 and RAD51 in homologous recombination repair, and XRCC7 in nonhomologous end joining double-strand break repair. Therefore, we tested the hypothesis that genetic polymorphisms in XRCC1, XRCC3, RAD51, XRCC7, and p53 were associated with risk of glioma in 309 patients with newly diagnosed glioma and 342 cancer-free control participants frequency matched on age (+/- 5 years), sex, and self-reported ethnicity. We did not find any statistically significant differences in the distributions of XRCC1 Arg399Gln, XRCC3 Thr241Met, RAD51 G135C, and P53 Arg72Pro polymorphisms between the cases and the controls. However, the XRCC7 G6721T variant T allele and TT genotype were more common in the cases (0.668 and 43.4%, respectively) than in the controls (0.613 and 38.9%, respectively), and the differences were statistically significant (P = 0.045 and 0.040, respectively). The adjusted odds ratios were 1.78 (95% confidence interval, 1.08-2.94) and 1.86 (95% confidence interval, 1.12-3.09) for the GT heterozygotes and TT homozygotes, respectively. The combined T variant genotype (GT+TT) was associated with a 1.82-fold increased risk of glioma (95% confidence interval, 1.13-2.93). These results suggest that the T allele may be a risk allele, and this XRCC7 polymorphism may be a marker for the susceptibility to glioma. Larger studies are needed to confirm our findings and unravel the underlying mechanisms.
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PMID:Polymorphisms of DNA repair genes and risk of glioma. 1531 91

Male germ cell apoptosis has been extensively explored in rodents. In contrast, very little is known about the susceptibility of developing germ cells to apoptosis in response to busulfan treatment. Spontaneous apoptosis of germ cells is rarely observed in the adult mouse testis, but under the experimental conditions described here, busulfan-treated mice exhibited a marked increase in apoptosis and a decrease in testis weight. TdT-mediated dUTP-X nicked end labeling analysis indicates that at one week following busulfan treatment, apoptosis was confined mainly to spermatogonia, with lesser effects on spermatocytes. The percentage of apoptosis-positive tubules and the apoptotic cell index increased in a time-dependent manner. An immediate effect was observed in spermatogonia within one week of treatment, and in the following week, secondary effects were observed in spermatocytes. RT-PCR analysis showed that expression of the spermatogonia-specific markers c-kit and Stra 8 was reduced but that Gli I gene expression remained constant, which is indicative of primary apoptosis of differentiating type A spermatogonia. Three and four weeks after busulfan treatment, RAD51 and FasL expression decreased to nearly undetectable levels, indicating that meiotic spermatocytes and post-meiotic cells, respectively, were lost. The period of germ cell depletion did not coincide with increased p53 or Fas/FasL expression in the busulfan-treated testis, although p110Rb phosphorylation and PCNA expression were inhibited. These data suggest that increased depletion of male germ cells in the busulfan-treated mouse is mediated by loss of c-kit/SCF signaling but not by p53- or Fas/FasL-dependent mechanisms. Spermatogonial stem cells may be protected from cell death by modulating cell cycle signaling such that E2F-dependent protein expression, which is critical for G1 phase progression, is inhibited.
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PMID:Murine male germ cell apoptosis induced by busulfan treatment correlates with loss of c-kit-expression in a Fas/FasL- and p53-independent manner. 1538 31

Homologous recombination (HR) is used in vertebrate somatic cells for essential, RAD51-dependent, repair of DNA double-strand-breaks (DSBs), but inappropriate HR can cause genome instability. A transcriptional transactivation-independent role for p53 in suppressing HR has been established, but is not detected in all HR assays. To address the basis of such exceptions, and the possibility that suppression by p53 may be discriminatory, we have conducted a controlled comparison of the effects of p53 depletion on three different kinds of HR. We show that, within the same cells, p53 depletion promotes both intra-chromosomal HR (ICHR) and extra-chromosomal HR (ECHR), but not homologous DNA integration (gene targeting; GT). This conclusion holds true for both spontaneous and DSB-induced ICHR and GT. We show further that non-conservative ICHR is more susceptible than conservative ICHR to inhibition by p53. These results provide strong evidence that p53 can discriminate between different forms of HR and, despite the fact that GT is used experimentally for gene disruption, is consistent with the possibility that p53 preferentially suppresses genome-destabilizing forms of HR. While the mechanism of suppression by p53 remains unclear, our data suggest that it is independent of mismatch repair and of changes in RAD51 protein levels.
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PMID:Discriminatory suppression of homologous recombination by p53. 1560 96


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