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)

p53 is thought to function in the maintenance of genomic stability by modulating transcription and interacting with cellular proteins to influence the cell cycle, DNA repair and apoptosis. p53 mutations occur in >50% of human cancers, and cells which lack wild type p53 accumulate karyotypic abnormalities such as amplifications, deletions, inversions and translocations. We propose that p53 hinders these promiscuous recombinational events by interacting with cellular recombination and repair machinery. We recently reported that p53 can directly bind in vivo to human Rad51 (hRad51) protein and in vitro to its bacterial homologue RecA. We used GST-fusion and his-tagged protein systems to further investigate the physical interaction between p53 and hRad51, homologue of the yeast Rad51 protein that is involved in recombination and DNA double strand repair. The hRad51 binds to wild-type p53 and to a lesser extent, point mutants 135Y, 249S and 273H. This binding is not mediated by a DNA or RNA intermediate. Mapping studies using a panel of p53 deletion mutants indicate that hRad51 could bind to two regions of p53; one between amino acids 94 and 160 and a second between 264 and 315. Addition of anti-p53 antibody PAb421 (epitope 372-381 amino acids) inhibited the interaction with hRad51. In contrast, p53 interacts with the region between aa 125 and 220 of hRad51, which is highly conserved among Rad51 related proteins from bacteria to human. In Escherichia coli ecA protein, this region is required for homo-oligomerization, suggesting that p53 might disrupt the interaction between RecA and Rad51 subunits, thus inhibiting biochemical functions of Rad51 like proteins. These data are consistent with the hypothesis that p53 interaction with hRAD51 may influence DNA recombination and repair and that additional modifications of p53 by mutation and protein binding may affect this interaction.
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PMID:Interaction of p53 with the human Rad51 protein. 938 May 10

Patients with the human disorder ataxia-telangiectasia (A-T; refs 1,2) and Atm-deficient mice have a pleiotropic phenotype that includes infertility. Here we demonstrate that male gametogenesis is severely disrupted in Atm-deficient mice in the earliest stages of meiotic prophase I, resulting in apoptotic degeneration. Atm is required for proper assembly of Rad51 onto the chromosomal axial elements during meiosis. In addition, p53, p21 and Bax are elevated in testes from Atm-deficient mice. To determine whether these elevated protein levels are important factors in the meiotic disruption of Atm-deficient mice, we analysed the meiotic phenotype of Atm/p53 or Atm/p21 double mutants. In these double mutants, meiosis progressed to later stages but was only partly rescued. Assembly of Rad51 foci on axial elements remained defective, and gametogenesis proceeded only to pachytene of prophase I. Previous results demonstrated that mice homozygous for a null mutation in Rad51 (ref. 6) display an early embryonic lethal phenotype that can be partly rescued by removing p53 and/or p21. Because Atm-deficient mice are viable but completely infertile, our studies suggest that the Rad51 assembly defects and elevated levels of p53, p21 and Bax represent tissue-specific responses to the absence of Atm.
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PMID:Partial rescue of the prophase I defects of Atm-deficient mice by p53 and p21 null alleles. 939 51

During the last years, homologues of E coli RecA have been cloned in numerous species including man. These Rad51 proteins share sequence as well as functional homologies with the bacterial protein. Human Rad51 (HsRad51) is able to catalyze strand exchange in vitro between homologous DNAs, but with a lower efficiency compared to that of RecA. This suggests the requirement of additional factors. A very interesting feature of Rad51 is its essential role in mouse which could mean that it has gained an essential function in cell growth. The interaction of HsRad51 with several tumor suppressor genes namely p53, BRCA1 and BRCA2 implies possible role(s) of this protein in tumorigenesis. Thus, the continued study of Rad51 should bring important insights not only into homologous recombination mechanisms but also into cell proliferation regulation.
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PMID:Mammalian Rad51 protein: a RecA homologue with pleiotropic functions. 946 96

The cellular response to DNA damage includes growth arrest and activation of DNA repair. Certain insights into how DNA damage is converted into intracellular signals that control the genotoxic stress response have been derived from the finding that the c-Abl protein tyrosine kinase is activated by ionizing radiation and other DNA-damaging agents. c-Abl associates with the DNA-dependent protein kinase (DNA-PK) and is activated by DNA-PK-dependent phosphorylation. The ataxia telangiectasia mutated (ATM) gene product also contributes to c-Abl activation. The demonstration that c-Abl binds to p53, induces the transactivation function of p53 and activates p21 expression has supported involvement of c-Abl in regulation of the p53-dependent G1 arrest response. Interaction between c-Abl and the Rad51 protein has also provided support for involvement of c-Abl in recombinational repair of DNA strand breaks. Defects in G1 arrest and repair predispose to replication of damaged templates and, in the event of irreparable DNA lesions, induction of apoptosis. The available evidence indicates that c-Abl effects a proapoptotic function by a mechanism largely independent of p53. c-Abl also functions as an upstream effector of the proapoptotic JNK/SAPK and p38 MAPK pathways. In addition, c-Abl-dependent inhibition of PI 3-kinase contributes to the induction of apoptosis. The findings thus suggest that, in response to genotoxic stress, c-Abl functions in determining cell fate, that is growth arrest and repair or induction of apoptosis. The physiologic function of c-Abl may reside in control of the cellular response to DNA strand breaks that occur during DNA replication, genetic recombination and gene rearrangements.
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PMID:Determination of cell fate by c-Abl activation in the response to DNA damage. 991 93

About half of the familial breast cancer cases are found to bear mutations in the breast cancer susceptibility gene 1 (BRCA1). The majority of BRCA1 mutations produce a truncated protein and BRCA1-associated breast tumors exhibit a number of defined tumor phenotypes. The function of BRCA1 has been examined in gene knockout mice in which the nullizygous mice die early in utero, but this lethality can be partially rescued by a nullizygous p53 mutation. Wild-type BRCA1 protein binds to a number of cellular proteins, including DNA repair protein Rad51, tumor suppressor p53, RNA polymerase II holoenzyme, RNA helicase A, CtBP-interacting protein, c-myc, BRCA1-associated RING domain protein (BARD1), BRCA2 protein, etc. These proteins likely mediate the involvement of BRCA1 in DNA repair, transcriptional transactivation, and cell cycle control. Overall, BRCA1 protein may act as a converging vehicle for cell regulatory proteins to associate with. Therefore, mutations in BRCA1 may affect the composition of these complexes on which dysregulation of cellular functions with eventual development of malignancy is expected.
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PMID:The functions of breast cancer susceptibility gene 1 (BRCA1) product and its associated proteins. 1019 18

Although it is clear that mammalian somatic cells possess the enzymatic machinery to perform homologous recombination of DNA molecules, the importance of this process in mitigating DNA damage has been uncertain. An initial genetic framework for studying homologous recombinational repair (HRR) has come from identifying relevant genes by homology or by their ability to correct mutants whose phenotypes are suggestive of recombinational defects. While yeast has been an invaluable guide, higher eukaryotes diverge in the details and complexity of HRR. For eliminating DSBs, HRR and end-joining pathways share the burden, with HRR contributing critically during S and G2 phases. It is likely that the removal of interstrand cross-links is absolutely dependent on efficient HRR, as suggested by the extraordinary sensitivity of the ercc1, xpf/ercc4, xrcc2, and xrcc3 mutants to cross-linking chemicals. Similarly, chromosome stability in untreated cells requires intact HRR, which may eliminate DSBs arising during DNA replication and thereby prevent chromosome aberrations. Complex regulation of HRR by cell cycle checkpoint and surveillance functions is suggested not only by direct interactions between human Rad51 and p53, c-Abl, and BRCA2, but also by very high recombination rates in p53-deficient cells.
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PMID:The contribution of homologous recombination in preserving genome integrity in mammalian cells. 1021 14

Human Rad51 (hRad51) has been found to be associated with BRCA1, BRCA2, and p53 either directly or indirectly and is one of at least eight human genes that are members of the Escherichia coli RecA/Saccharomyces cerevisiae Rad51 family thought to affect genomic stability through DNA recombination/repair processes. While inactivation of DNA mismatch repair clearly leads to instability of repeated sequences and to an increased risk for tumorigenesis, such a parallel for the RecA family members has not been reported. Recently, a high frequency of loss of heterozygosity at chromosome 15q14-15, near the genomic region containing hRad51, has been reported in human tumors (W. Wick et al., Oncogene, 12: 973-978, 1996). To determine whether hRad51 inactivation may be involved in the etiology of these tumors, we have characterized the hRad51 genetic locus and mapped it to chromosome 15q14-15 within the central region of loss of heterozygosity. However, single-strand conformational polymorphism analysis and direct sequencing of tumors did not reveal any mutations in the hRad51 coding sequence or intron/exon boundaries. We also examined the DNA methylation status of a CpG-rich region in the putative hRad51 promoter region. No indication of hypermethylation was found. These results suggest that hRad51 is not a tumor suppressor because it is either an essential gene, redundant gene and/or independent of the BRCA1/BRCA2 tumor suppressor pathway(s).
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PMID:Characterization of the human Rad51 genomic locus and examination of tumors with 15q14-15 loss of heterozygosity (LOH). 1049 8

Human Rec2/Rad51L1 is a member of the Rad51 family of proteins. Although recombinase activity, typical of this family, could not be established, its overexpression in mammalian cells has been shown to cause a delay in G1. Moreover, since hsRec2/Rad51L1 has been found to be induced by both ionizing and UV irradiation, it is likely that hsRec2/Rad51L1 is elevated following any DNA damage and causes a G1 delay to allow time for DNA repair to occur. Limited homology with catalytic domains X and XI of protein kinase A suggested that kemptide, an artificial substrate containing one phosphorylatable residue, a serine, might serve as a substrate for hsRec2/Rad51L1. Here, we report that hsRec2/Rad51L1 can phosphorylate kemptide, as well as myelin basic protein, p53, cyclin E, and cdk2, but not a peptide substrate containing tyrosine only. The finding that hsRec2/Rad51L1 exhibits protein kinase activity is a first step toward identifying a mechanism whereby this protein affects the cell cycle.
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PMID:HsRec2/Rad51L1, a protein influencing cell cycle progression, has protein kinase activity. 1062 63

Several newly identified tumor suppressor genes including ATM, NBS1, BRCA1 and BRCA2 are involved in DNA double-strand break repair (DSBR) and DNA damage-induced checkpoint activation. Many of the gene products involved in checkpoint control and DSBR have been studied in great detail in yeast. In addition to evolutionarily conserved proteins such as Chk1 and Chk2, studies in mammalian cells have identified novel proteins such as p53 in executing checkpoint control. DSBR proteins including Mre11, Rad50, Rad51, Rad54, and Ku are present in yeast and in mammals. Many of the tumor suppressor gene products interact with these repair proteins as well as checkpoint regulators, thus providing a biochemical explanation for the pleiotropic phenotypes of mutant cells. This review focuses on the proteins mediating G1/S, S, and G2/M checkpoint control in mammalian cells. In addition, mammalian DSBR proteins and their activities are discussed. An intricate network among DNA damage signal transducers, cell cycle regulators and the DSBR pathways is illustrated. Mouse knockout models for genes involved in these processes have provided valuable insights into their function, establishing genomic instability as a major contributing factor in tumorigenesis.
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PMID:DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis. 1063 Jun 41

The xeroderma pigmentosum variant (XPV) is a genetic disease involving high levels of solar-induced cancer that has normal excision repair but shows defective DNA replication after UV irradiation because of mutations in the damage-specific polymerase hRAD30. We previously found that the induction of sister chromatid exchanges by UV irradiation was greatly enhanced in transformed XPV cells, indicating the activation of a recombination pathway. We now have identified that XPV cells make use of a homologous recombination pathway involving the hMre11/hRad50/Nbs1 protein complex, but not the Rad51 recombination pathway. The hMre11 complexes form at arrested replication forks, in association with proliferating cell nuclear antigen. In x-ray-damaged cells, in contrast, there is no association between hMre11 and proliferating cell nuclear antigen. This recombination pathway assumes greater importance in transformed XPV cells that lack a functional p53 pathway and can be detected at lower frequencies in excision-defective XPA fibroblasts and normal cells. DNA replication arrest after UV damage, and the associated S phase checkpoint, is therefore a complex process that can recruit a recombination pathway that has a primary role in repair of double-strand breaks from x-rays. The symptoms of elevated solar carcinogenesis in XPV patients therefore may be associated with increased genomic rearrangements that result from double-strand breakage and rejoining in cells of the skin in which p53 is inactivated by UV-induced mutations.
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PMID:Polymerase eta deficiency in the xeroderma pigmentosum variant uncovers an overlap between the S phase checkpoint and double-strand break repair. 1085 52


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