Xeroderma pigmentosum group C in an isolated region of Guatemala.
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ABSTRACT:
SUBMITTER: Cleaver JE
PROVIDER: S-EPMC3031115 | biostudies-literature | 2007 Feb
REPOSITORIES: biostudies-literature
Publications
Xeroderma pigmentosum group C in an isolated region of Guatemala.
Cleaver James E JE Feeney Luzviminda L Tang Jean Y JY Tuttle Peggy P
The Journal of investigative dermatology 20060921 2
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Project description:Purpose:Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder characterized by increased susceptibility to UV radiation- (UVR-) induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Eight different genes are affected, and the prevalence of the disease differs across the world. The present study describes the main ophthalmologic features and symptoms in patients with XP in this case series. Methods:Patients were examined consecutively at the University Hospital of the Federal University of Goias between January 2016 and June 2018. All patients underwent ophthalmologic examination and were asked about their ophthalmological history and the presence of ocular symptoms. Results:Twenty-one patients with genetic confirmation were evaluated. The genetic variants XPV and XPC were detected in the patients. The most prevalent findings include eyelid changes, observed in 80.9% of the patients, and ocular surface changes as punctate keratopathy, occurring in 16 patients (76.2%), corneal neovascularization, and corneal opacities. Six patients (28.5%) presented corneoconjunctival tumor. More than half of patients had previous history of treatment of ocular neoplasia. Ocular burning was the most reported symptom. Conclusions:The ocular characteristics identified in this study corroborate the existing literature, mainly related to the surface. Concerning the XP variant and the gravity of ocular signs, XPC has earlier and more severe symptoms than XPV. Due to their relative rarity, publications of XP cases are important to understand the possible damages caused by the disease in the eyes and surrounding area.
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Project description:UV-damaged DNA-binding protein (UV-DDB) is composed of two subunits, DDB1 (p127) and DDB2 (p48). Mutations in the DDB2 gene inactivate UV-DDB in individuals from complementation group E of xeroderma pigmentosum (XP-E), an autosomal recessive disease characterized by sun sensitivity, severe risk for skin cancer and defective nucleotide excision repair. UV-DDB is also deficient in many rodent tissues, exposing a shortcoming in rodent models for cancer. In vitro, UV-DDB binds to cyclobutane pyrimidine dimers (CPDs), 6-4 photoproducts and other DNA lesions, stimulating the excision of CPDs, and to a lesser extent, of 6-4 photoproducts. In vivo, UV-DDB plays an important role in the p53-dependent response of mammalian cells to DNA damage. When cells are exposed to UV, the resulting accumulation of p53 activates DDB2 transcription, which leads to increased levels of UV-DDB. Binding of UV-DDB to CPDs targets these lesions for global genomic repair, suppressing mutations without affecting UV survival. Apparently, cells are able to survive with unrepaired CPDs because of the activity of bypass DNA polymerases. Finally, there is evidence that UV-DDB may have roles in the cell that are distinct from DNA repair.
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Project description:The cellular defense system known as global-genome nucleotide excision repair (GG-NER) safeguards genome stability by eliminating a plethora of structurally unrelated DNA adducts inflicted by chemical carcinogens, ultraviolet (UV) radiation or endogenous metabolic by-products. Xeroderma pigmentosum group C (XPC) protein provides the promiscuous damage sensor that initiates this versatile NER reaction through the sequential recruitment of DNA helicases and endonucleases, which in turn recognize and excise insulting base adducts. As a DNA damage sensor, XPC protein is very unique in that it (a) displays an extremely wide substrate range, (b) localizes DNA lesions by an entirely indirect readout strategy, (c) recruits not only NER factors but also multiple repair players, (d) interacts avidly with undamaged DNA, (e) also interrogates nucleosome-wrapped DNA irrespective of chromatin compaction and (f) additionally functions beyond repair as a co-activator of RNA polymerase II-mediated transcription. Many recent reports highlighted the complexity of a post-translational circuit that uses polypeptide modifiers to regulate the spatiotemporal activity of this multiuse sensor during the UV damage response in human skin. A newly emerging concept is that stringent regulation of the diverse XPC functions is needed to prioritize DNA repair while avoiding the futile processing of undamaged genes or silent genomic sequences.
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Project description:Xeroderma pigmentosum complementation group C (XPC) is a DNA damage recognition protein essential for initiation of global-genomic nucleotide excision repair (GG-NER). Humans carrying germline mutations in the XPC gene exhibit strong susceptibility to skin cancer due to defective removal via GG-NER of genotoxic, solar UV-induced dipyrimidine photoproducts. However, XPC is increasingly recognized as important for protection against non-dermatologic cancers, not only through its role in GG-NER, but also by participating in other DNA repair pathways, in the DNA damage response and in transcriptional regulation. Additionally, XPC expression levels and polymorphisms likely impact development and may serve as predictive and therapeutic biomarkers in a number of these non-dermatologic cancers. Here we review the existing literature, focusing on the role of XPC in non-dermatologic cancer development, progression, and treatment response, and highlight possible future applications of XPC as a prognostic and therapeutic biomarker.
| S-EPMC9069926 | biostudies-literature
Project description:XPC is a 940-residue multidomain protein critical for the sensing of aberrant DNA and initiation of global genome nucleotide excision repair. The C-terminal portion of XPC (residues 492-940; XPC-C) has critical interactions with DNA, RAD23B, CETN2, and TFIIH, whereas functional roles have not yet been assigned to the N-terminal portion (residues 1-491; XPC-N). In order to analyze the molecular basis for XPC function and mutational defects associated with xeroderma pigmentosum (XP) disease, a series of stable bacterially expressed N- and C-terminal fragments were designed on the basis of sequence analysis and produced for biochemical characterization. Limited proteolysis experiments combined with mass spectrometry revealed that the full XPC-C is stable but XPC-N is not. However, a previously unrecognized folded helical structural domain was found within XPC-N, XPC(156-325). Pull-down and protease protection assays demonstrated that XPC(156-325) physically interacts with the DNA repair factor XPA, establishing the first functional role for XPC-N. XPC-C exhibits binding characteristics of the full-length protein, including stimulation of DNA binding by physical interaction with RAD23B and CETN2. Analysis of an XPC missense mutation (Trp690Ser) found in certain patients with XP disease revealed that this mutation is associated with a diminished ability to bind DNA. Evidence of contributions to protein interactions from regions in both XPC-N and XPC-C along with recently recognized homologies to yeast PNGase prompted construction of a structural model of a folded XPC core. This model offers key insights into how domains from the two portions of the protein may cooperate in generating specific XPC functions.
| S-EPMC2579963 | biostudies-literature
Project description:Xeroderma pigmentosum group C (XPC) protein initiates the DNA excision repair of helix-distorting base lesions. To understand how this versatile subunit searches for aberrant sites within the vast background of normal genomic DNA, the real-time redistribution of fluorescent fusion constructs was monitored after high-resolution DNA damage induction. Bidirectional truncation analyses disclosed a surprisingly short recognition hotspot, comprising approximately 15% of human XPC, that includes two beta-hairpin domains with a preference for non-hydrogen-bonded bases in double-stranded DNA. However, to detect damaged sites in living cells, these DNA-attractive domains depend on the partially DNA-repulsive action of an adjacent beta-turn extension that promotes the mobility of XPC molecules searching for lesions. The key function of this dynamic interaction surface is shown by a site-directed charge inversion, which results in increased affinity for native DNA, retarded nuclear mobility and diminished repair efficiency. These studies reveal a two-stage discrimination process, whereby XPC protein first deploys a dynamic sensor interface to rapidly interrogate the double helix, thus forming a transient recognition intermediate before the final installation of a more static repair-initiating complex.
| S-EPMC2735174 | biostudies-literature
Project description:Nucleotide excision repair (NER) is the most versatile DNA repair system that removes bulky DNA damage induced by various endogenous and exogenous factors, including UV radiation. Defects in NER can lead to the xeroderma pigmentosum (XP) syndrome, mainly characterized by increased carcinogenesis in the skin. The function of NER factors, including xeroderma pigmentosum group C (XPC), can be regulated by post-translational modifications such as ubiquitination. However, the role of phosphorylation in XPC function remains unknown. Here, we show that phosphorylation of XPC acts as a novel post-translational regulatory mechanism of the NER pathway. We show that XPC is phosphorylated at serine 94. Moreover, after UVB irradiation, XPC phosphorylation regulates recruitment of ubiquitinated XPC and its downstream NER factors to the chromatin. In addition, upon evaluating the predicted kinases for XPC phosphorylation, we found that casein kinase II (CK2) promotes NER. Furthermore, CK2 kinase mediates XPC phosphorylation at serine 94, and also promotes recruitment of ubiquitinated XPC to the chromatin after UVB irradiation. Our findings have identified XPC phosphorylation as a new mechanism for regulating NER following UV-induced DNA damage.
| S-EPMC6007576 | biostudies-literature
Project description:Xeroderma pigmentosum-Cockayne syndrome complex is a very rare multisystem degenerative disorder (Orpha: 220295; OMIM: 278730, 278760, 278780, 610651). Published information on XP-CS is mostly scattered throughout the literature. We compiled statistics related to symptom prevalence in XP-CS and have written a clinical description of the syndrome. We also drew on clinical practices used in XP and in Cockayne syndrome without XP to aid management of XP-CS.Extensive searches of the literature identified 43 XP-CS patients. The diagnosis had been confirmed with molecular or biochemical methods in 42 of them. Clinical features of each patient were summarized in spreadsheets and summary statistics were generated from this data. XP patients are classified into complementation groups according to the gene that is mutated. There are four groups in XP-CS, and classification was available for 42 patients. Twenty-one were in the XP-G complementation group, 13 in XP-D, 5 in XP-B, and 3 in XP-F. Overall, the clinical features of XP-CS are very similar to those of CS without XP, with the exception of skin cancers in XP-CS. However, one intriguing finding was that cancer incidence was lower in XP-CS compared to XP alone or XP-neurological disorder. The cancer rate in XP-CS was higher than in CS without XP, an unsurprising finding. There is preliminary evidence for the existence of severity groups in XP-CS, as is the case in CS.Although health problems in XP-CS vary both in severity and in when they the first occur, there was overall homogeneity between all complementation groups and putative severity groups. Severely affected patients met fewer milestones and died at younger ages compared to more mildly affected patients.
| S-EPMC5379700 | biostudies-literature
Project description:BackgroundNumerous studies have assessed the association between xeroderma pigmentosum complementation group C (XPC) polymorphisms and susceptibility of prostate cancer (PCa); however, the findings remain inconsistent.MethodsWe performed an updated analysis utilizing data from electronic databases to obtain a more accurate estimation of the relationship between XPC rs2228001 A/C polymorphism and PCa risk. We further used in silico tools to investigate this correlation.ResultsTotally, 5,305 PCa cases and 6,499 control subjects were evaluated. When all studies pooled together, we detected no positive result (recessive genetic model: OR = 1.14, 95% CI = 0.93-1.40, Pheterogeneity = 0.001, P = .212); nevertheless, the XPC rs2228001 A/C variant was associated with PCa risk in Asian descendants in the subgroup analysis (OR = 1.21, 95% CI = 1.01-1.43, Pheterogeneity = 0.008, P = .034). In silico tools showed that more than 20 proteins can participate in the protein crosstalk with XPC. The expression of XPC was down-regulated in all Gleason scores of prostate cancer.ConclusionsThe present study indicated that the XPC rs2228001 A/C variant may be associated with elevated PCa risk in Asian patients.
| S-EPMC7521337 | biostudies-literature
Project description:This study was designed to learn if asymptomatic heterozygotes with mutations in a DNA repair gene are at an increased risk for cancer. To examine this, we focused on carriers of an XPA founder mutation because the frequency of xeroderma pigmentosum (XP) patients is much greater among Japanese than Caucasians, more than half of Japanese XP patients are affected at the XPA gene, and the majority of XP-A patients carry the same founder mutation in the XPA gene. Here we show that the frequency of XPA heterozygote was 14/1698 (0.8%) in cancer-free controls, and the corresponding frequency in patients with nonmelanocytic skin cancer that developed in sun-exposed areas was 11/440 (2.5%, OR = 3.08, p = 0.0097) for basal cell carcinoma, and 3/272 (1.1%, OR = 1.34, p = 0.72) for squamous cell carcinoma. These results suggest a moderately elevated risk for skin cancer among XPA heterozygotes.
| S-EPMC8057111 | biostudies-literature