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)

BLM, WRN, and p53 are involved in the homologous DNA recombination pathway. The DNA structure-specific helicases, BLM and WRN, unwind Holliday junctions (HJ), an activity that could suppress inappropriate homologous recombination during DNA replication. Here, we show that purified, recombinant p53 binds to BLM and WRN helicases and attenuates their ability to unwind synthetic HJ in vitro. The p53 248W mutant reduces abilities of both to bind HJ and inhibit helicase activities, whereas the p53 273H mutant loses these abilities. Moreover, full-length p53 and a C-terminal polypeptide (residues 373-383) inhibit the BLM and WRN helicase activities, but phosphorylation at Ser(376) or Ser(378) completely abolishes this inhibition. Following blockage of DNA replication, Ser(15) phospho-p53, BLM, and RAD51 colocalize in nuclear foci at sites likely to contain DNA replication intermediates in cells. Our results are consistent with a novel mechanism for p53-mediated regulation of DNA recombinational repair that involves p53 post-translational modifications and functional protein-protein interactions with BLM and WRN DNA helicases.
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PMID:The processing of Holliday junctions by BLM and WRN helicases is regulated by p53. 1208 66

Werner syndrome is a rare autosomal recessive disorder involving the premature appearance of features reminiscent of human aging. Werner syndrome occurs by mutation of the WRN gene, encoding a DNA helicase. WRN contributes to the induction of the p53 tumor suppressor protein by various DNA damaging agents. Here we show that UV exposure leads to extensive translocation of WRN from the nucleolus to nucleoplasmic foci in a dose-dependent manner. Ionizing radiation also induces WRN translocation, albeit milder, partially through activation of the ATM kinase. The nucleoplasmic foci to which WRN is recruited display partial colocalization with PML nuclear bodies. The translocation of WRN into nucleoplasmic foci is significantly enhanced by the protein deacetylase inhibitor, Trichostatin A. Moreover, Trichostatin A delays the re-entry of WRN into the nucleolus at late times after irradiation. WRN is acetylated in vivo, and this is markedly stimulated by the acetyltransferase p300. Importantly, p300 augments the translocation of WRN into nucleoplasmic foci. These findings support the notion that WRN plays a role in the cellular response to DNA damage and suggest that the activity of WRN is modulated by DNA damage-induced post-translational modifications of WRN and possibly WRN-interacting proteins.
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PMID:DNA damage-induced translocation of the Werner helicase is regulated by acetylation. 1238 94

RecQ family DNA helicases are defined as proteins sharing a homologous region with Escherichia coli RecQ and are basically regarded as enzymes involved in recombination. Humans have five RecQ family members, and deficiencies in three of them, BLM, WRN, and RTS, cause Bloom's, Werner's, and Rothmund-Thomson syndromes, respectively, each characterized by genomic instability and cancer predisposition. In this context, an important function of the RecQ homologs appears to be the unwinding of intermediates of recombination, thereby preventing its uncontrolled execution. As a consequence, their deficiencies give rise to elevated levels of recombination (the hyper-recombination phenotype), which result in chromosomal aberrations including loss of heterozygosity, a common chromosomal change associated with malignancies. Thus, those helicases qualify as caretaker-type tumor suppressor proteins. In addition, BLM and WRN deficiencies have been shown to attenuate p53-mediated apoptosis, suggesting that they also belong to the gatekeeper class of tumor suppressor proteins.
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PMID:RecQ family helicases: roles as tumor suppressor proteins. 1248 16

Werner-syndrome fibroblasts have a reduced in vitro life span before entering replicative senescence. Although this has been thought to be causal in the accelerated ageing of this disease, controversy remains as to whether Werner syndrome is showing the acceleration of a normal cellular ageing mechanism or the occurrence of a novel Werner-syndrome-specific process. Here, we analyse the signalling pathways responsible for senescence in Werner-syndrome fibroblasts. Cultured Werner-syndrome (AG05229) fibroblasts senesced after approximately 20 population doublings with most of the cells having a 2N content of DNA. This was associated with hypophosphorylated pRb and high levels of p16(Ink4a) and p21(Waf1). Senescent AG05229 cells re-entered the cell cycle following microinjection of a p53-neutralizing antibody. Similarly, production of the human papilloma virus 16 E6 oncoprotein in presenescent AG05229 cells resulted in senescence being bypassed and extended cellular life span. Werner-syndrome fibroblasts expressing E6 did not proliferate indefinitely but reached a second proliferative lifespan barrier, termed M(int), that could be bypassed by forced production of telomerase in post-M1 E6-producing cells. The conclusions from these studies are that: (1) replicative senescence in Werner-syndrome fibroblasts is a telomere-induced p53-dependent event; and (2) the intermediate lifespan barrier M(int) is also a telomere-induced event, although it appears to be independent of p53. Werner-syndrome fibroblasts resemble normal human fibroblasts for both these proliferative lifespan barriers, with the strong similarity between the signalling pathway linking telomeres to cell-cycle arrest in Werner-syndrome and normal fibroblasts providing further support for the defect in Werner syndrome causing the acceleration of a normal ageing mechanism.
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PMID:Telomere-based proliferative lifespan barriers in Werner-syndrome fibroblasts involve both p53-dependent and p53-independent mechanisms. 1261 76

Repeat expansion diseases such as fragile X syndrome (FXS) result from increases in the size of a specific tandem repeat array. In addition to large expansions, small changes in repeat number and deletions are frequently seen in FXS pedigrees. No mouse model accurately recapitulates all aspects of this instability, particularly the occurrence of large expansions. This may be due to differences between mice and humans in CIS and/or TRANS-acting factors that affect repeat stability. The identification of such factors may help reveal the expansion mechanism and allow the development of suitable animal models for these disorders. We have examined the effect of age, dietary folate, and mutations in the Werner's syndrome helicase (WRN) and TRP53 genes on FXS repeat instability in mice. WRN facilitates replication of the FXS repeat and enhances Okazaki fragment processing, thereby reducing the incidence of processes that have been suggested to lead to expansion. p53 is a protein involved in DNA damage surveillance and repair. We find two types of repeat instability in these mice, small changes in repeat number that are seen at frequencies approaching 100%, and large deletions which occur at a frequency of about 10%. The frequency of these events was independent of WRN, p53, parental age, or folate levels. The large deletions occur at the same frequency in mice homozygous and heterozygous for the repeat suggesting that they are not the result of an interallelic recombination event. In addition, no evidence of large expansions was seen. Our data thus show that the absence of repeat expansions in mice is not due to a more efficient WRN protein or p53-mediated error correction mechanism, and suggest that these proteins, or the pathways in which they are active, may not be involved in expansion in humans either. Moreover, the fact that contractions occur in the absence of expansions suggests that these processes occur by different mechanisms.
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PMID:Instability of the fragile X syndrome repeat in mice: the effect of age, diet and mutations in genes that affect DNA replication, recombination and repair proficiency. 1452 74

Mutations in the WRN or the TP53 genes lead to spontaneous genetic instability, an elevated risk of tumor formation, and sensitivity to compounds that interfere with DNA replication, such as camptothecin and DNA interstrand cross-linking drugs. We investigated the hypothesis that WRN and TP53 are involved in cellular responses to DNA replication-blocking lesions by exposing WRN deficient and TP53 mutant lymphoblastoid cell lines (LCLs) to 1-beta-d-arabinofuranosylcytosine (AraC) and bleomycin. Loss of WRN or TP53 function resulted in induction of apoptosis and lesser proliferative survival in response to AraC and bleomycin. WRN and TP53 operate in a shared DNA damage response pathway, since in cells in which TP53 was inactivated by SV-40 transformation, no difference in AraC and bleomycin sensitivity was found regardless of WRN status. In contrast to TP53 mutant LCLs, WRN-deficient cells showed unaffected cell cycle arrest after AraC and bleomycin exposure, which indicates that WRN is not involved in DNA damage-activated cell cycle arrest. Neither WRN nor TP53 deficiency affected cellular recovery from exposure to AraC and bleomycin, which disagrees with a direct role in repair of these DNA lesions. Our results indicate that WRN and TP53 perform different functions in a shared DNA damage response pathway.
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PMID:Distinct functions for WRN and TP53 in a shared pathway of cellular response to 1-beta-D-arabinofuranosylcytosine and bleomycin. 1514 62

Werner syndrome (WS) fibroblasts enter replicative senescence after a reduced in vitro life span. Although this has been postulated as causal in the accelerated aging seen in this disease, controversy remains as to whether WS is showing the acceleration of a normal cellular aging mechanism or, instead, the occurrence of a novel WS-specific process. To address this, we analyzed the signaling pathways involved in senescence in WS fibroblasts. Cultured WS fibroblasts underwent senescence after approximately 20 population doublings, with the majority of the cells having a 2N DNA content. This was associated with high levels of the CdkIs p16 and p21. Senescent WS cells reentered the cell cycle after microinjection of a p53-neutralizing antibody. Similarly, presenescent WS fibroblasts expressing the E6 and/or E7 oncoproteins bypassed M1 and ultimately reached a second proliferative life span barrier, which strongly resembled the second life span barriers found in normal cells for growth dynamics, cellular morphology, and expression of p16 and p21. The strong similarity between the signaling pathways triggering cell cycle arrest in WS and normal fibroblasts provides support for the defect in WS causing the acceleration of a normal aging mechanism and validates the use of WS as a model for some aspects of human aging.
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PMID:Investigation of the signaling pathways involved in the proliferative life span barriers in werner syndrome fibroblasts. 1524 28

Normal human diploid fibroblasts (HDFs) exposed to a single H(2)O(2) subcytotoxic stress display features of premature senescence, termed stress-induced premature senescence (SIPS). In this work, our aim was to study SIPS in Werner syndrome (WS) fibroblasts, derived from a patient with WS, a disease resembling accelerated aging. The subcytotoxic dose for WS fibroblasts was found to be inferior to that of normal HDFs, indicating WS fibroblasts are more sensitive to hydrogen peroxide than normal HDFs. SA beta-gal activity has been shown to occur both in vitro and in vivo, and we studied the proportion of WS cells positive for SA beta-gal. Intriguingly, the percentage of positive cells did not increase with the dose of H(2)O(2) used. Contrary to other HDFs, the DNA-binding activity of p53 in WS fibroblasts did not increase in SIPS. We found, based on our results, that WS fibroblasts feature an altered stress response and do not reach SIPS from H(2)O(2). We suggest that the proportion of cells that in normal HDFs would enter SIPS instead die in WS fibroblasts. Last, we propose that aging derives from a loss of integrity of the chromatin structure, which occurs faster in WS patients.
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PMID:No increase in senescence-associated beta-galactosidase activity in Werner syndrome fibroblasts after exposure to H2O2. 1524 48

Genetic interventions that accelerate or retard aging in mice are crucial in advancing our knowledge over mammalian aging. Yet determining if a given intervention affects the aging process is not straightforward since, for instance, many disease-causing mutations may decrease life span without affecting aging. In this work, we employed the Gompertz model to determine whether several published interventions previously claimed to affect aging in mice do indeed alter the aging process. First, we constructed age-specific mortality tables for a number of mouse cohorts used in longevity experiments and calculated the rate at which mortality increases with age. Estimates of age-independent mortality were also calculated. We found no statistical evidence that GHRHR, IGF1R, INSR, PROP1, or TRX delay or that ATM + TERC, BubR1, klotho, LMNA, PRDX1, p53, WRN + TERC, or TOP3B accelerate mouse aging. Often, changes in the expression of these genes affected age-independent mortality and so they may prove useful to other aspects of medicine. We found statistical evidence that C/EBP, MSRA, SHC1, growth hormone, GHR, PIT1, and PolgA may influence aging in mice. These results were interpreted together with age-related physiological and pathological changes and provide novel insights regarding the role of several genes in the mammalian aging process.
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PMID:The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging. 1546 29

The tumor suppressor protein p53 is emerging as a central regulator of homologous recombination (HR) processes and DNA replication. P53 may downregulate HR through multiple mechanisms including the reported associations with the Rad51 and Rad54 recombinases, and the BLM and WRN helicases. Here, we investigated whether the interaction of p53 with human replication protein A (RPA) is necessary for the regulation of HR. By employing a plasmid-based HR assay in p53-null H1299 lung carcinoma cells, we studied the HR-suppressing properties of a panel of p53 mutants, which varied in their ability to interact with RPA. Both wild-type p53 and a transactivation-deficient p53 mutant (L22Q/W23S) suppressed HR and prevented RPA binding to ssDNA in vitro and in vivo. Conversely, p53 mutations that specifically disrupt the RPA-binding domain, while not compromising p53 transactivation function (D48H/D49H and W53S/F54S), did not affect HR. Suppression of HR was also not seen with missense mutations in the p53 core domain (His175 and His273), which retained the ability to interact with RPA, suggesting that the disruption of additional binding interactions of p53, for example, with Rad51 or recombination intermediates, also impacts on HR. We hypothesize that sequestration of RPA by p53 at the sites of recombination is one means by which p53 can inhibit HR processes. Our data support and extend the previously formulated 'dual model' of p53's role as guardian of the genome.
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PMID:The interaction of p53 with replication protein A mediates suppression of homologous recombination. 1548 3


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