UMLS:C0043346 - FACTA Search

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Query: UMLS:C0043346 (xeroderma pigmentosum)
2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Damaged DNA-binding protein, DDB, is a heterodimer of p127 and p48 with a high specificity for binding to several types of DNA damage. Mutations in the p48 gene that cause the loss of DDB activity were found in a subset of xeroderma pigmentosum complementation group E (XP-E) patients and have linked to the deficiency in global genomic repair of cyclobutane pyrimidine dimers (CPDs) in these cells. Here we show that with a highly defined system of purified repair factors, DDB can greatly stimulate the excision reaction reconstituted with XPA, RPA, XPC.HR23B, TFIIH, XPF.ERCC1 and XPG, up to 17-fold for CPDs and approximately 2-fold for (6-4) photoproducts (6-4PPs), indicating that no additional factor is required for the stimulation by DDB. Transfection of the p48 cDNA into an SV40-transformed human cell line, WI38VA13, was found to enhance DDB activity and the in vivo removal of CPDs and 6-4PPs. Furthermore, the combined technique of recently developed micropore UV irradiation and immunostaining revealed that p48 (probably in the form of DDB heterodimer) accumulates at locally damaged DNA sites immediately after UV irradiation, and this accumulation is also observed in XP-A and XP-C cells expressing exogenous p48. These results suggest that DDB can rapidly translocate to the damaged DNA sites independent of functional XPA and XPC proteins and directly enhance the excision reaction by core repair factors.
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PMID:DDB accumulates at DNA damage sites immediately after UV irradiation and directly stimulates nucleotide excision repair. 1170 87

Human damaged DNA-binding protein (DDB) is a heterodimer of p48/DDB2 and p127/DDB1 subunits. Mutations in DDB2 are responsible for Xeroderma Pigmentosum group E, but no mutants of mammalian DDB1 have been described. To study DDB1, the Schizosaccharomyces pombe DDB1 sequence homologue (ddb1(+)) was cloned, and a ddb1 deletion strain was constructed. The gene is not essential; however, mutant cells showed a 37% impairment in colony-forming ability, an elongated phenotype, and abnormal nuclei. The ddb1Delta strain was sensitive to UV irradiation, X-rays, methylmethane sulfonate, and thiabendazole, and these sensitivities were compared with those of the well characterized rad13Delta, rhp51Delta, and cds1Delta mutant strains. Ddb1p showed nuclear and nucleolar localization, and the aberrant nuclear structures observed in the ddb1Delta strain suggest a role for Ddb1p in chromosome segregation.
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PMID:Characterization of a Schizosaccharomyces pombe strain deleted for a sequence homologue of the human damaged DNA binding 1 (DDB1) gene. 1218 26

The human DDB1 and DDB2 genes encode the 127 and 48 kDa subunits, respectively, of the damage-specific DNA-binding protein (DDB). Mutations in the DDB2 gene have been correlated with the hereditary disease xeroderma pigmentosum group E. We have investigated the proximal promoters of the DDB genes, both of which are G/C-rich and do not contain a TATA box. Transient expression analysis in HeLa cells using a luciferase reporter system indicated the presence of core promoters located within 292 bp (DDB1) and 220 bp (DDB2) upstream of the putative transcription initiation sites. Both core promoters contain multiple active Sp1 sites, with those of DDB1 at -123 to -115 and of DDB2 at -29 to -22 being critical determinants of promoter activity. In addition, an N-myc site at -56 to -51 for DDB1 is an essential transcription element, and mutations in a DDB1 NF-1 site at -104 to -92, a DDB2 NF-1 site at -68 to -56 and a DDB2 E2F site at +36 to +43 also reduce promoter activity. Taken together, these results suggest a regulation of basal transcription typical of cell cycle-regulated genes, and therefore support conjectures that the DDB heterodimer and/or its subunits have functions other than direct involvement in DNA repair.
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PMID:Basal transcriptional regulation of human damage-specific DNA-binding protein genes DDB1 and DDB2 by Sp1, E2F, N-myc and NF1 elements. 1252 63

DDB (damaged DNA-binding protein) is a heterodimer, comprised of p48 (DDB2) and p127 (DDB1) subunits, which has a high affinity for a variety of DNA lesions including UV-photoproducts. The mutations in DDB2 gene have been found in a subset of xeroderma pigmentosum complementation group E patients. However, no natural mutation has been identified so far in the cDNA of human DDB1 and the precise roles of DDB1 are still unknown. We have cloned the DDB1 cDNA from the chicken B lymphocyte line DT40 and revealed an open reading frame of 3420 bp encoding a polypeptide of 1140 amino acids, which is identical in size to the orthologs of human, monkey, mouse, rat and Drosophila melanogaster in databases. The amino acid sequence deduced from the chicken DDB1 cDNA shows a high homology to the mammalian DDB1 orthologs (96-97% identity). Northern blot analysis using 5' portion of the chicken DDB1 cDNA as a probe detected a single transcript of ~ 4.3 kb in chicken DT40 cells as well as in human HeLa cells and mouse embryonic fibroblasts. Furthermore, the chicken DDB1 (tagged with enhanced GFP) transiently expressed in human cells mainly localized in the cytoplasm, and coexpression of human DDB2 dramatically changed the localization from the cytoplasm to nucleus. These results suggest that DDB1 is evolutionarily conserved in the primary structure and function, and may play a fundamental role in higher eukaryotes.
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PMID:cDNA cloning of the chicken DDB1 gene encoding the p127 subunit of damaged DNA-binding protein. 1277 17

The expression from a reporter construct driven by a cytomegalovirus (CMV) immediate early (IE) promoter is strongly inducible by UV in human fibroblasts. This response is induced at lower UV fluences in transcription-coupled repair (TCR)-deficient fibroblasts compared with normal fibroblasts and is absent in their simian virus 40-transformed counterparts. In this study we demonstrate that expression of human papilloma virus (HPV) E7 (but not of HPV E6) can attenuate UV-induced expression from the human CMV-IE-driven reporter construct in human fibroblasts. Furthermore, UV-induced expression from the reporter construct appears impaired in murine fibroblasts harboring inactivating mutations in the retinoblastoma (Rb) gene family members p107 and pRb but not in fibroblasts harboring such mutations in the p53 gene. Taken together, these data suggest that one or more members of the pRb family (but not p53) play an essential role in mediating UV-induced expression from the CMV-IE promoter. In this study we report normal UV-upregulation of reporter expression in xeroderma pigmentosum (XP) group E fibroblasts, consistent with normal TCR. Because XP-E cells deficient in the p48 subunit of the damaged DNA-binding protein are impaired in E2F-1-activated transcription, these results also suggest that the (pRb-regulated) transcription factor E2F-1 does not play an essential role in UV-enhanced expression from the CMV-IE promoter.
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PMID:Role for retinoblastoma protein family members in UV-enhanced expression from the human cytomegalovirus immediate early promoters. 1287 Aug 48

Xeroderma pigmentosum (XP) complementation group E gene product, damaged DNA-binding protein 2 (DDB2), is a subunit of the DDB heterodimeric protein complex with high specificity for binding to a variety of DNA helix-distorting lesions. DDB is believed to play a role in the initial step of damage recognition in mammalian nucleotide excision repair (NER) of ultraviolet light (UV)-induced photolesions. It has been shown that DDB2 is rapidly degraded after cellular UV irradiation. However, the relevance of DDB2 degradation to its functionality in NER is still unknown. Here, we have provided evidence that Cullin 4A (CUL-4A), a key component of CUL-4A-based ubiquitin ligase, mediates DDB2 degradation at the damage sites and regulates the recruitment of XPC and the repair of cyclobutane pyrimidine dimers. We have shown that CUL-4A can be identified in a UV-responsive protein complex containing both DDB subunits. CUL-4A was visualized in localized UV-irradiated sites together with DDB2 and XPC. Degradation of DDB2 could be blocked by silencing CUL-4A using small interference RNA or by treating cells with proteasome inhibitor MG132. This blockage resulted in prolonged retention of DDB2 at the subnuclear DNA damage foci within micropore irradiated cells. Knock down of CUL-4A also decreased recruitment of the damage recognition factor, XPC, to the damaged foci and concomitantly reduced the removal of cyclobutane pyrimidine dimers from the entire genome. These results suggest that CUL-4A mediates the proteolytic degradation of DDB2 and that this degradation event, initiated at the lesion sites, regulates damage recognition by XPC during the early steps of NER.
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PMID:Cullin 4A-mediated proteolysis of DDB2 protein at DNA damage sites regulates in vivo lesion recognition by XPC. 1652 7

In mammalian nucleotide excision repair (NER) operating throughout the genome, DNA lesions are recognized by protein factors that specifically bind to the damaged sites. Such damage recognition factors involve the xeroderma pigmentosum group C (XPC) protein complex and ultraviolet (UV)-damaged DNA-binding protein (UV-DDB). To assess specific DNA-binding activities of these factors, it is useful to take advantage of biochemical assays using DNA substrates that contain a defined lesion and/or artificial structure in a site-specific manner. In addition, it has been shown that both XPC and UV-DDB are ubiquitylated in response to UV irradiation of cells. This ubiquitylation is mediated by ubiquitin ligase associated with UV-DDB and is important for the NER process of UV-induced lesions. Methods for detecting the UV-DDB-dependent ubiquitylation in vivo and in vitro are also described.
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PMID:The xeroderma pigmentosum group C protein complex and ultraviolet-damaged DNA-binding protein: functional assays for damage recognition factors involved in global genome repair. 1679 69

UV-damaged-DNA-binding protein (UV-DDB) is a heterodimer comprised of DDB1 and DDB2 and integrated in a complex that includes a ubiquitin ligase component, cullin 4A, and Roc1. Here we show that the ubiquitin ligase activity of the DDB2 complex is required for efficient global genome nucleotide excision repair (GG-NER) in chromatin. Mutant DDB2 proteins derived from xeroderma pigmentosum group E patients are not able to mediate ubiquitylation around damaged sites in chromatin. We also found that CSN, a negative regulator of cullin-based ubiquitin ligases, dissociates from the DDB2 complex when the complex binds to damaged DNA and that XPC and Ku oppositely regulate the ubiquitin ligase activity, especially around damaged sites. Furthermore, the DDB2 complex-mediated ubiquitylation plays a role in recruiting XPA to damaged sites. These findings shed some light on the early stages of GG-NER.
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PMID:DDB2 complex-mediated ubiquitylation around DNA damage is oppositely regulated by XPC and Ku and contributes to the recruitment of XPA. 2036 62

We studied the thermodynamic properties, conformation, and recognition of DNA duplexes site-specifically modified by monofunctional adducts of Ru(II) complexes of the type [Ru(II)(eta(6)-arene)(Cl)(en)](+), in which arene=para-, meta-, or ortho-terphenyl (complexes 1, 2, and 3, respectively) and en=1,2-diaminoethane. It has been shown (J. Med. Chem. 2008, 51, 5310) that 1 exhibits promising cytotoxic effects in human tumor cells, whereas 2 and 3 are much less cytotoxic; concomitantly with the high cytotoxicity of 1, its DNA binding mode involves combined intercalative and monofunctional (coordination) binding modes, whereas less cytotoxic compounds 2 and 3 bind to DNA only through a monofunctional coordination to DNA bases. An analysis of conformational distortions induced in DNA by adducts of 1 and 2 revealed more extensive and stronger distortion and concomitantly greater thermodynamic destabilization of DNA by the adducts of nonintercalating 2. Moreover, affinity of replication protein A to the DNA duplex containing adduct of 1 was pronouncedly lower than to the adduct of 2. On the other hand, another damaged-DNA-binding protein, xeroderma pigmentosum protein A, did not recognize the DNA adduct of 1 or 2. Importantly, the adducts of 1 induced a considerably lower level of repair synthesis than the adducts of 2, which suggests enhanced persistence of the adducts of the more potent and intercalating 1 in comparison with the adducts of the less potent and nonintercalating 2. Also interestingly, the adducts of 1 inhibited DNA polymerization more efficiently than the adducts of 2, and they could also be bypassed by DNA polymerases with greater difficulty. Results of the present work along with those previously published support the view that monodentate Ru(II) arene complexes belong to a class of anticancer agents for which structure-pharmacological relationships might be correlated with their DNA-binding modes.
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PMID:Energetics, conformation, and recognition of DNA duplexes modified by monodentate Ru(II) complexes containing terphenyl arenes. 2037 25

Nucleotide excision repair (NER) is the principal pathway that removes helix-distorting deoxyribonucleic acid (DNA) damage from the mammalian genome. Recognition of DNA lesions by xeroderma pigmentosum group C (XPC) protein in chromatin is stimulated by the damaged DNA-binding protein 2 (DDB2), which is part of a CUL4A-RING ubiquitin ligase (CRL4) complex. In this paper, we report a new function of DDB2 in modulating chromatin structure at DNA lesions. We show that DDB2 elicits unfolding of large-scale chromatin structure independently of the CRL4 ubiquitin ligase complex. Our data reveal a marked adenosine triphosphate (ATP)-dependent reduction in the density of core histones in chromatin containing UV-induced DNA lesions, which strictly required functional DDB2 and involved the activity of poly(adenosine diphosphate [ADP]-ribose) polymerase 1. Finally, we show that lesion recognition by XPC, but not DDB2, was strongly reduced in ATP-depleted cells and was regulated by the steady-state levels of poly(ADP-ribose) chains.
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PMID:DDB2 promotes chromatin decondensation at UV-induced DNA damage. 2249 24

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