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)

Ultraviolet light (UV light) induces helix distorting DNA lesions that pose a block to replicative DNA polymerases. Recovery from this replication arrest is reportedly impaired in nucleotide excision repair (NER)-deficient xeroderma pigmentosum (XP) fibroblasts and primary fibroblasts lacking functional p53. These independent observations suggested that the involvement of p53 in the recovery from UV-induced replication arrest was related to its role in regulating the global genomic subpathway of NER (GG-NER). Using primary human fibroblasts, we confirm that the recovery from UV-induced replication arrest is impaired in cells lacking functional p53 and in primary XP fibroblasts derived from complementation groups A or C (XP-A and XP-C) that are defective in GG-NER. Surprisingly, DNA synthesis recovered normally in GG-NER-deficient XP complementation group E (XP-E) cells that carry mutations in the p53 regulated DNA repair gene DDB2 and are specifically defective in the repair of cyclobutane pyrimidine dimers (CPD) but not pyrimidine (6-4) pyrimidone photoproducts. Disruption of p53 in these XP-E fibroblasts prevented the recovery from UV-induced replication arrest. Therefore, the roles of p53 and GG-NER in the recovery from UV-induced replication are separable and DDB2-independent. These results further indicate that primary human fibroblasts expressing functional p53 efficiently replicate DNA containing CPD whereas p53-deficient cells do not, consistent with a role for p53 in permitting translesion synthesis of these DNA lesions.
 ...
PMID:DDB2-independent role for p53 in the recovery from ultraviolet light-induced replication arrest. 1763 May 10

The xeroderma pigmentosum group E gene product DDB2, a protein involved in nucleotide excision repair (NER), associates with the E3 ubiquitin ligase complex Cul4A-DDB1. But the precise role of these interactions in the NER activity of DDB2 is unclear. Several models, including DDB2-mediated ubiquitination of histones in UV-irradiated cells, have been proposed. But those models lack clear genetic evidence. Here we show that DDB2 participates in NER by regulating the cellular levels of p21(Waf1/Cip1). We show that DDB2 enhances nuclear accumulation of DDB1, which binds to a modified form of p53 containing phosphorylation at Ser18 (p53(S18P)) and targets it for degradation in low-dose-UV-irradiated cells. DDB2(-/-) mouse embryonic fibroblasts (MEFs), unlike wild-type MEFs, are deficient in the proteolysis of p53(S18P). Accumulation of p53(S18P) in DDB2(-/-) MEFs causes higher expression p21(Waf1/Cip1). We show that the increased expression of p21(Waf1/Cip1) is the cause NER deficiency in DDB2(-/-) cells because deletion or knockdown of p21(Waf1/Cip1) reverses their NER-deficient phenotype. p21(Waf1/Cip1) was shown to bind PCNA, which is required for both DNA replication and NER. Moreover, an increased level of p21(Waf1/Cip1) was shown to inhibit NER both in vitro and in vivo. Our results provide genetic evidence linking the regulation of p21(Waf1/Cip1) to the NER activity of DDB2.
 ...
PMID:The xeroderma pigmentosum group E gene product DDB2 activates nucleotide excision repair by regulating the level of p21Waf1/Cip1. 1796 71

While many p53-deficient cell types are impaired in global genomic nucleotide excision repair of cyclobutane pyrimidine dimers (CPDs), human epidermal keratinocytes expressing human papillomavirus type 16 E6 and E7 are p53 deficient and yet maintain repair of CPD. We hypothesized that the p53 homolog, p63, may participate in governing global repair instead of p53 in keratinocytes. Following ultraviolet radiation (UVR) of E6/E7 keratinocytes, depletion of p63 but not of p73 impaired global genomic repair of CPD relative to control cells. In all cases, repair of pyrimidine(6-4)pyrimidone photoproducts, the other major UVR-induced DNA lesions, was unaffected. In E6/E7 keratinocytes treated with p63 small interfering RNA, reduced global repair of CPD was associated not with reduced levels of messenger RNA-encoding DNA damage recognition proteins but rather with decreased levels of DDB2 and XPC proteins, suggesting that p63 posttranscriptionally regulates levels of these proteins. These results indicate that global repair may be regulated at multiple levels and suggest a novel role for p63 in modulating repair of DNA damage in human keratinocytes. The results may provide insight into mechanisms of genomic stability in epithelia infected with oncogenic human papilloma viruses and may further explain the lack of increased skin cancer incidence in Li-Fraumeni syndrome.
 ...
PMID:Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63. 1798 11

The p53R2 ribonucleotide reductase subunit is a p53-inducible protein involved in DNA repair and mitochondrial DNA replication. It has been shown that p53 is activated by nitric oxide, which can damage DNA at high concentrations. This suggests that NO may regulate p53R2 expression through p53 activation. We show here that NO increases p53 protein expression in p53-wt cell lines and upregulates p53R2 at the protein and mRNA levels in a p53-dependent manner. Other p53 target genes, such as DDB2, WAF1 and PCNA, are also induced by NO. Surprisingly, p53R2 is similarly upregulated by NO in two p53-deficient cell lines, showing the existence of p53-independent regulatory mechanisms. Delta Np73, which is overexpressed in many cancers, inhibits the transcriptional activity of p53 and p53 homologs. In p53-wt cells, the Delta Np73alpha isoform inhibits basal and NO-induced p53R2 protein expression. In p53-null cells, it also strongly inhibits p53R2 expression, and represses the enhancer activity of the p53-responsive element present in the p53R2-encoding gene. These results demonstrate that p53R2 expression can be controlled by p53 homologs in the absence of p53, and is downregulated by oncogenic Delta Np73 isoforms. Knocking down p53R2 in p53-wt cells dramatically enhances NO-induced DNA damages, indicating a protective function of the p53R2 ribonucleotide reductase subunit in prevention or repair of NO-mediated genotoxic injury.
 ...
PMID:Upregulation of the p53R2 ribonucleotide reductase subunit by nitric oxide. 1847 60

The objective of this study was to evaluate the time-course effects of UV-B exposure on expression of genes involved in the DNA repair system of zebrafish (Danio rerio) hepatocytes, a highly competent species in terms of damage repair induced by UV radiation. For gene expression analysis (RT-PCR), cells were exposed to 23.3 mJ cm(-2) UV-B, which was the dose that affected viable cell number (reduction of 30% when compared with the control group) and produced no visual alteration on cell morphology. The early response observed (6 h) showed induction in the expression of the CDKI gene (cyclin-dependent kinase inhibitor) and genes related to DNA damage repair (mainly XPC and DDB2), while the late response observed (24 h) was more related to up-regulation of p53 and genes involved in cell cycle arrest (gadd45a, cyclinG1). In all times analyzed, the anti-apoptotic gene Bcl-2 was down-regulated. Another interesting result observed was the up-regulation of the Apex-1 gene after UV-B exposure, which could indicate the induction of oxidative lesions in the DNA molecule. In conclusion, these results demonstrate an activation of the DNA repair system in hepatocytes of zebrafish exposed to UV-B radiation, mainly involving the participation of p53.
 ...
PMID:Time-course expression of DNA repair-related genes in hepatocytes of zebrafish (Danio rerio) after UV-B exposure. 1876 2

The p53 tumour suppressor is a transcription factor that can either activate or repress the expression of specific genes in response to cellular stresses such as exposure to ultraviolet light. The p53 protein can exert both pro- and anti-apoptotic effects depending on cellular context. In primary human fibroblasts, p53 protects cells from UV-induced apoptosis at moderate doses but this is greatly affected by the nucleotide excision repair (NER) capacity of the cells. The damage-specific DNA binding protein 2 (DDB2) is involved in NER and is associated with xeroderma pigmentosum subgroup E (XP-E). Importantly, DDB2 is also positively regulated by the p53 protein. To study the potential interplay between DDB2 and p53 in determining the apoptotic response of primary fibroblasts exposed to UV light, the expression of these proteins was manipulated in primary normal and XP-E fibroblast strains using human papillomavirus E6 protein (HPV-E6), RNA interference and recombinant adenoviruses expressing either p53 or DDB2. Normal and XP-E fibroblast strains were equally sensitive to UV-induced apoptosis over a broad range of doses and disruption of p53 in these strains using HPV-E6 or RNA interference led to a similar increase in apoptosis following exposure to UV light. In contrast, forced expression of p53 or DDB2 did not affect UV-induced apoptosis greatly in these normal or XP-E fibroblast strains. Collectively, these results indicate that p53 is primarily protective against UV-induced apoptosis in primary human fibroblasts and this activity of p53 does not require DDB2.
 ...
PMID:The anti-apoptotic role for p53 following exposure to ultraviolet light does not involve DDB2. 1942 72

Sunlight UV exposure produces DNA photoproducts in skin that are repaired solely by nucleotide excision repair in humans. A significant fraction of melanomas are thought to result from UV-induced DNA damage that escapes repair; however, little evidence is available about the functional capacity of normal human melanocytes, malignant melanoma cells, and metastatic melanoma cells to repair UV-induced photoproducts in DNA. In this study, we measured nucleotide excision repair in both normal melanocytes and a panel of melanoma cell lines. Our results show that in 11 of 12 melanoma cell lines tested, UV photoproduct repair occurred as efficiently as in primary melanocytes. Importantly, repair capacity was not affected by mutation in the N-RAS or B-RAF oncogenes, nor was a difference observed between a highly metastatic melanoma cell line (A375SM) or its parental line (A375P). Lastly, we found that although p53 status contributed to photoproduct removal efficiency, its role did not seem to be mediated by enhanced expression or activity of DNA binding protein DDB2. We concluded that melanoma cells retain capacity for nucleotide excision repair, the loss of which probably does not commonly contribute to melanoma progression.
 ...
PMID:Similar nucleotide excision repair capacity in melanocytes and melanoma cells. 2050 36

Due to its link with human pathologies, including cancer, the mechanism of Nucleotide Excision Repair (NER) has been extensively studied. Most of the pathway and players have been defined using in vitro reconstitution experiments. However, in vivo, the NER machinery must deal with the presence of organized chromatin, which in some regions, such as heterochromatin, is highly condensed but still susceptible to DNA damage. A series of events involving different chromatin-remodeling factors and histone-modifying enzymes target chromatin regions that contain DNA lesions. CPDs change the structure of the nucleosome, allowing access to factors that can recognize the lesion. Next, DDB1-DDB2 protein complexes, which mono-ubiquitinate histones H2A, H3, and H4, recognize nucleosomes containing DNA lesions. The ubiquitinated nucleosome facilitates the recruitment of ATP-dependent chromatin-remodeling factors and the XPC-HR23B-Centrin 2 complex to the target region. Different ATP-dependent chromatin-remodeling factors, such as SWI/SNF and INO80, have been identified as having roles in the UV irradiation response prior to the action of the NER machinery. Subsequently, remodeling of the nucleosome allows enzymatic reactions by histone-modifying factors that may acetylate, methylate or demethylate specific histone residues. Intriguingly, some of these histone modifications are dependent on p53. These histone modifications and the remodeling of the nucleosome allow the entrance of TFIIH, XPC and other NER factors that remove the damaged strand; then, gap-filling DNA synthesis and ligation reactions are carried out after excision of the oligonucleotide with the lesion. Finally, after DNA repair, the initial chromatin structure has to be reestablished. Therefore, factors that modulate chromatin dynamics contribute to the NER mechanism, and they are significant in the future design of treatments for human pathologies related to genome instability and the appearance of drug-resistant tumors.
 ...
PMID:Open, repair and close again: chromatin dynamics and the response to UV-induced DNA damage. 2113 Jul 13

Cellular protection against deleterious effects of DNA damaging agents requires an intricate network of defense mechanisms known as the DNA damage response (DDR). Ionizing radiation (IR) mediated activation of the DDR induces a transcriptional upregulation of genes that are also involved in nucleotide excision repair (NER). This suggests that pre-exposure to X-rays might stimulate NER in human cells. Here, we demonstrate in normal human fibroblasts that UV-induced NER is augmented by pre-exposure to IR and that this increased repair is accompanied by elevated mRNA and protein levels of the NER factors XPC and DDB2. Furthermore, when IR exposure precedes local UV irradiation, the presence of XPC and DDB2 at the sites of local UV damages is increased. This increase might be p53 dependent, but the mechanism of X-ray specific stabilization of p53 is unclear as both X-rays and UV stabilize p53.
 ...
PMID:Enhanced nucleotide excision repair in human fibroblasts pre-exposed to ionizing radiation. 2201 41

The p53 tumor suppressor is a DNA-damage-responsive sequence-specific transcriptional activator. The sustained activation of the p53 response is incompatible with cell growth and viability. To circumvent this issue, a variety of negative feedback loops exist to limit the duration of p53 activation. Despite our understanding of p53 regulation, very little is known about the effect of transient p53 activation on the long-term expression of p53 target genes. Here we used a temperature-sensitive variant of p53 and oligonucleotide microarrays to monitor gene expression during and following reversible p53 activation. The expression of most p53-induced transcripts was rapidly reversible, consistent with active mRNA decay. Representative 3' UTRs derived from short-lived transcripts (i.e., DDB2 and GDF15) conferred instability on a heterologous mRNA, while 3' UTRs derived from more stable transcripts (i.e., CRYAB and TP53I3) did not. The 3' UTRs derived from unstable p53-induced mRNAs were significantly longer than those derived from stable mRNAs. These 3' UTRs had high uridine and low cytosine content, leading to a higher density of U-, AU-, and GU-rich sequences. Remarkably, short-lived p53 targets were induced faster, reaching maximum transcript levels earlier than the stable p53 targets. Taken together, the evidence indicates that the p53 transcriptional response has evolved with primarily short-lived target mRNAs and that post-transcription processes play a prominent role in the p53 response.
 ...
PMID:The role of mRNA decay in p53-induced gene expression. 2202 Sep 75


<< Previous 1 2 3 4 5 6 Next >>