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

Bloom's syndrome is a rare autosomal recessive genetic disorder characterized by chromosomal aberrations, genetic instability, and cancer predisposition, all of which may be the result of abnormal signal transduction during DNA damage recognition. Here, we show that BLM is an intermediate responder to stalled DNA replication forks. BLM colocalized and physically interacted with the DNA damage response proteins 53BP1 and H2AX. Although BLM facilitated physical interaction between p53 and 53BP1, 53BP1 was required for efficient accumulation of both BLM and p53 at the sites of stalled replication. The accumulation of BLM/53BP1 foci and the physical interaction between them was independent of gamma-H2AX. The active Chk1 kinase was essential for both the accurate focal colocalization of 53BP1 with BLM and the consequent stabilization of BLM. Once the ATR/Chk1- and 53BP1-mediated signal from replicational stress is received, BLM functions in multiple downstream repair processes, thereby fulfilling its role as a caretaker tumor suppressor.
 ...
PMID:Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest. 1536 58

Repair of DSBs is important to prevent chromosomal fragmentation, translocations and deletions. To investigate the process in NHEJ, we have established an in vitro system to clarify the measurement and analysis of the efficiency and the fidelity of rejoining of DSBs, and applied the method to investigate NHEJ in human cells derived from patients suffering from cancer-prone hereditary diseases. A DSB was introduced in plasmid pZErO-2 at a specific site within the ccdB gene that is lethal to E. coli cells, and treated with nuclear extracts from human cells. The efficiency of rejoining in the nuclear extract from an A-T cell line was comparable to that from a control cell line. However, the accuracy of rejoining was much lower for the A-T cell extract than for the control cell extract. All mutations were deletions, most of which contained short direct repeats at the breakpoint junctions. The deletion spectrum caused by the A-T nuclear extract was distinct from that by the control extract. These results indicate that A-T cells have certain deficiencies in end-joining of double-strand breaks in DNA. The extract from BS cells also showed the similar activity and the lower fidelity of rejoing compared to that from normal cells. From the sequencing analysis of the junction of DSBs, it is speculated that the defect in the BLM helicase might cause irregular rejoining of DSBs. Radioadaptive response is the acquirement of cellular resistance to ionizing radiation by prior exposure to low dose. We investigated the in vitro end-joining activity of DNA ends in radioadaptive cells. Both the efficiency and the fidelity of rejoining in the cells pre-exposed to low dose are increased comparing to those without pre-exposure. We also investigated the joining activity of DNA ends in p53-deficient cells. Pre-irradiation caused no apparent alteration in both the efficiency and fidelity of end-joining. These results suggest that the exposure to low dose activates a cellular function to repair DSBs efficiently, which is dependent on p53. These results indicate that NHEJ pathway is regulated by many factors; genetic regulation by ATM and BLM, and physiological conditions such as irradiation with ionizing radiation. The observations also suggest that in some occasions p53 might play a key role in NHEJ.
 ...
PMID:Genetic and physiological regulation of non-homologous end-joining in mammalian cells. 1547 91

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.
 ...
PMID:The interaction of p53 with replication protein A mediates suppression of homologous recombination. 1548 3

Repair of DSBs is important to prevent chromosomal fragmentation, translocations and deletions. To investigate the process in NHEJ, we have established an in vitro system to clarify the measurement and analysis of the efficiency and the fidelity of rejoining of DSBs, and applied the method to investigate NHEJ in human cells derived from patients suffering from cancer-prone hereditary diseases. A DSB was introduced in plasmid pZErO-2 at a specific site within the ccdB gene that is lethal to E. coli cells, and treated with nuclear extracts from human cells. The efficiency of rejoining in the nuclear extract from an A-T cell line was comparable to that from a control cell line. However, the accuracy of rejoining was much lower for the A-T cell extract than for the control cell extract. All mutations were deletions, most of which contained short direct repeats at the breakpoint junctions. The deletion spectrum caused by the A-T nuclear extract was distinct from that by the control extract. These results indicate that A-T cells have certain deficiencies in end-joining of double-strand breaks in DNA. The extract from BS cells also showed the similar activity and the lower fidelity of rejoing compared to that from normal cells. From the sequencing analysis of the junction of DSBs, it is speculated that the defect in the BLM helicase might cause irregular rejoining of DSBs. Radioadaptive response is the acquirement of cellular resistance to ionizing radiation by prior exposure to low dose. We investigated the in vitro end-joining activity of DNA ends in radioadaptive cells. Both the efficiency and the fidelity of rejoining in the cells pre-exposed to low dose are increased comparing to those without pre-exposure. We also investigated the joining activity of DNA ends in p53-deficient cells. Pre-irradiation caused no apparent alteration in both the efficiency and fidelity of end-joining. These results suggest that the exposure to low dose activates a cellular function to repair DSBs efficiently, which is dependent on p53. These results indicate that NHEJ pathway is regulated by many factors; genetic regulation by ATM and BLM, and physiological conditions such as irradiation with ionizing radiation. The observations also suggest that in some occasions p53 might play a key role in NHEJ.
 ...
PMID:Genetic and physiological regulation of non-homologous end-joining in mammalian cells. 1549 26

Exposure to DNA-damaging agents can elicit a variety of stress-related responses that may alter the gene expression of numerous biological pathways. We used Affymetrix microarrays to detect gene expression changes in mouse lymphoma (L5178Y) and human lymphoblastoid (TK6) cells in response to methyl methanesulfonate (MMS; a prototypical alkylating agent) and bleomycin (a prototypical oxidative mutagen). Cells were treated for 4 hr, and RNA was isolated either at the end of the treatment or after a 20-hr recovery period. Two concentrations of each agent were used based on cytotoxicity levels and Tk mutant frequencies. Our microarray data analysis indicated that MMS and bleomycin gene expression responses were considerably different in mouse cells versus human cells. The results also suggested that more comprehensive cellular responses to MMS and bleomycin occurred in TK6 cells than in L5178Y cells. In contrast to L5178Y cells, the response of TK6 cells to MMS and bleomycin was characterized by the induction of p53-dependent genes that are involved in DNA repair, cell cycle regulation, and apoptosis. It appears that the induction of DNA damage by MMS in human TK6 cells mediated cytotoxicity and led to decreased cell survival. This may explain the greater sensitivity of TK6 cells to cytotoxic effects of MMS compared to L5178Y cells. Bleomycin exerted comparable cytotoxic effects in the two cell lines. Overall, these studies were unable to identify distinctive gene expression changes that differentiated bleomycin from MMS in either TK6 cells or mouse lymphoma cells.
 ...
PMID:Comparison of gene expression changes induced in mouse and human cells treated with direct-acting mutagens. 1551 72

The BLM helicase, a deficiency that markedly increases cancer incidence in humans, is required for optimal repair during DNA replication. We show that BLM rapidly moves from PML nuclear bodies to damaged replication forks, returning to PML bodies several hours later, owing to activities of the DNA damage response kinases ATR and ATM, respectively. Immunofluorescence and cellular fractionation demonstrate that BLM partitions to different sub-cellular compartments after replication stress. Unexpectedly, fibroblasts lacking BLM were deficient in phospho-ATM (S-1981) and 53-binding protein-1 (53BP1), and these proteins failed to form foci following replication stress. Expression of a dominant p53 mutant or helicase-deficient BLM restored replication stress-induced 53BP1 foci, but only mutant p53 restored optimal ATM activation. Thus, optimal repair of damaged replication fork lesions likely requires both ATR and ATM. BLM recruits 53BP1 to these lesions independent of its helicase activity, and optimal activation of ATM requires both p53 and BLM helicase activities.
 ...
PMID:ATR and ATM-dependent movement of BLM helicase during replication stress ensures optimal ATM activation and 53BP1 focus formation. 1553 48

RECQ4 is a member of the RecQ helicase family, which has been implicated in the regulation of DNA replication, recombination and repair. p53 modulates the functions of RecQ helicases including BLM and WRN. In this study, we demonstrate that p53 can regulate the transcription of RECQ4. Using nontransformed, immortalized normal human fibroblasts, we show that p53-dependent downregulation of RECQ4 expression occurred in G1-arrested cells, both in the absence or presence of exogenous DNA damage. Wild-type p53 (but not the tumor-derived mutant forms) repressed RECQ4 promoter activity. The camptothecin or etoposide-dependent p53-mediated repression was attenuated by trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs). Repression of the RECQ4 promoter was accompanied with an increased accumulation of HDAC1, and the loss of SP1 and p53 binding to the promoter. The simultaneous formation of a camptothecin-dependent p53-SP1 complex indicated its occurrence outside of the RECQ4 promoter. These data suggest that p53-mediated repression of RECQ4 transcription during DNA damage results from the modulation of the promoter occupancy of transcription activators and repressors.
 ...
PMID:Tumor suppressor p53 represses transcription of RECQ4 helicase. 1567 34

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive deposition of extracellular matrix in the affected skin as well as various internal organs, vascular injury and immune abnormality; however, the etiology of SSc remains still unknown. We previously established an experimental mouse model for scleroderma by repeated local injections of bleomycin, a DNA damaging agent. In this study, we examined the induction of apoptosis and the expression of p53, p21 (Waf1/Cip1), and proliferating cell nuclear antigen (PCNA) in the lesional skin following bleomycin exposure in this model. Dermal sclerosis was induced by alternate day's injections of bleomycin for 4 weeks. TUNEL assay showed that apoptotic cells began to appear at 1 week after bleomycin exposure, and were prominently detected at 3-4 weeks. Immunohistochemical examination showed increased expression of p53 and p21 mainly in the infiltrating mononuclear cells at 2 weeks after bleomycin treatment. Bleomycin treatment markedly enhanced PCNA expression at 1-2 weeks, mainly in mesenchyme, as compared with control phosphate buffered saline treatment. Reverse transcriptase-polymerase chain reaction analysis showed that the expression of p53 and p21 mRNA was concurrently upregulated at 1-2 weeks after bleomycin treatment. Taken together, coordinate increased levels of p53 and p21 preceded the maximal induction of apoptosis and dermal sclerosis. Our findings suggest that apoptotic processes are involved in the pathophysiology of bleomycin-induced scleroderma, which may be mediated, in part, by the upregulation of p53 and p21.
 ...
PMID:Increased expression of p53 and p21 (Waf1/Cip1) in the lesional skin of bleomycin-induced scleroderma. 1580 28

Phosphorylation of p53 on serine 15 by ATM or ATR is a frequent modification and initiates a cascade of post-translational modifications. To identify possible mechanisms that modulate p53 functions in recombination surveillance, we compared the nuclear localization of p53 phosphorylated on serine 15 (p53pSer15) and the key enzymes of homologous recombination (HR) after replication fork stalling. We demonstrate an almost mutually exclusive subcompartmentalization with Rad52, while p53pSer15 was colocalizing with 40-60% of the Rad51 and Mre11 foci. Therefore, possible sites of p53pSer15-dependent regulation seem to be sites of Rad51- rather than Rad52-dependent HR processes. Remarkably, the association of p53pSer15 with repair complexes containing Rad51 or Mre11 was transient, because less than 20% of the Rad51 and Mre11 foci overlapped with p53pSer15 after 6 h. When we examined colocalization and co-immunoprecipitation of p53pSer15 and the RecQ helicase BLM with recombination surveillance and proapoptotic functions, we observed colocalization within a fraction of approximately 70% of the BLM foci and stable physical interactions until 6 h after replication arrest. Our data suggest that p53pSer15 plays a dual role in the functional interactions with early complexes of Rad51-dependent recombination and with BLM-associated surveillance and signalling complexes within distinct nuclear subcompartments.
 ...
PMID:Differences in the association of p53 phosphorylated on serine 15 and key enzymes of homologous recombination. 1580 45

A subset of DNA helicases, the RecQ family, has been found to be associated with the p53-mediated apoptotic pathway and is involved in maintaining genomic integrity. This family contains the BLM and WRN helicases, in which germline mutations are responsible for Bloom and Werner syndromes, respectively. TFIIH DNA helicases, XPB and XPD, are also components in this apoptotic pathway. We hypothesized that there may be some redundancy between helicases in their ability to complement the attenuated p53-mediated apoptotic levels seen in cells from individuals with diseases associated with these defective helicase genes. The attenuated apoptotic phenotype in Bloom syndrome cells was rescued not only by ectopic expression of BLM, but also by WRN or XPB, both 3' --> 5' helicases, but not expression of the 5' --> 3' helicase XPD. Overexpression of Sgs1, a WRN/BLM yeast homolog, corrected the reduction in BS cells only, which is consistent with Sgs1 being evolutionarily most homologous to BLM. A restoration of apoptotic levels in cells from WS, XPB or XPD patients was attained only by overexpression of the specific helicase. Our data suggest a limited redundancy in the pathways of these RecQ helicases in p53-induced apoptosis.
 ...
PMID:Redundancy of DNA helicases in p53-mediated apoptosis. 1628 11


<< Previous 1 2 3 4 5 6 7 8 9 Next >>