Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytogenetic studies of a skin squamous cell carcinoma from a xeroderma pigmentosum patient were performed at several passages. They show the existence of recurrent rearrangements: 53% were dicentrics, of which 67% were of the telomere-telomere type. The telomeric region of the long arm of chromosome 12 was the most involved (in 38% of dicentrics), followed by 22p. The origin of this type of jumping rearrangement and its possible role on cell proliferation are discussed.
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PMID:Jumping end-to-end dicentrics in a case of squamous cell carcinoma from a patient with xeroderma pigmentosum. 275 4

The ERCC2 (excision repair cross-complementing rodent repair group 2) gene product is involved in transcription-coupled repair as an integral member of the basal transcription factor BTF2/TFIIH complex. Defects in this gene can result in three distinct human disorders, namely the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. We report the comparative analysis of 91.6 kb of new sequence including 54.3 kb encompassing the human ERCC2 locus, the syntenic region in the mouse (32.6 kb), and a further 4.7 kb of sequence 3' of the previously reported ERCC2 region in the hamster. In addition to ERCC2, our analysis revealed the presence of two previously undescribed genes in all three species. The first is centromeric (in the human) to ERCC2 and is most similar to the kinesin light chain gene in sea urchin. The second gene is telomeric (in the human) to ERCC2 and contains a motif found in ankyrins, some cell cycle proteins, and transcription factors. Multiple EST matches to this putative new gene indicate that it is expressed in several human tissues, including breast. The identification and description of two new genes provides potential candidate genes for disorders mapping to this region of 19q13.2.
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PMID:Sequence analysis of the ERCC2 gene regions in human, mouse, and hamster reveals three linked genes. 878 41

Growth characteristics, karyotype changes, and telomere length variations were analyzed during the life span of 12 anchorage-independent clones isolated from a xeroderma pigmentosum fibroblast strain. After an initial period of comparable active growth, all the clones showed a decline in the growth rate and finally entered a phase of replicative senescence; however, the number of population doublings and the time required to enter senescence varied among the clones. Repeated cytogenetic analyses during culture propagation showed the appearance of chromosome anomalies, mainly telomeric association (tas) and unbalanced translocations. In all the clones the percentage of abnormal mitoses increased with culture passage, but reached different levels (from less than 10% to about 100%). This finding indicates that the replicative block may be associated with differently altered cytogenetic patterns. Specific chromosome arms (5p, 16q, 19q, and 20q) were preferentially involved in tas, suggesting that alterations in chromosome ends may occur which predispose to fusion. In some clones it was possible to demonstrate the origin of marker chromosomes from the evolution of tas. Telomere length analysis by Southern blotting on DNA samples prepared from 7 clones and from the parental cell lines showed that the terminal restriction fragment (TRF) profiles were homogeneous in senescent parental cells and in the clones during the last part of their life in culture, regardless of the degree of karyotype abnormalities. The homogeneity of the TRF profiles supports the hypothesis of a critical telomere length at senescence.
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PMID:Chromosomal instability and telomere length variations during the life span of human fibroblast clones. 936 22

A specialized nucleotide excision repair pathway known as transcription-coupled repair (TCR) counteracts the toxic effects of DNA damage in transcriptionally active genes. The clustering of active genes into gene-rich chromosomal domains predicts that the sites of TCR are unevenly distributed through the genome. To elucidate the genomic organization and chromosomal localization of TCR, we isolated DNA fragments encompassing TCR-mediated repair sites from UV-C irradiated xeroderma pigmentosum group C cells, which can only repair the transcribed strand of active genes. This DNA was used as a molecular probe to visualize TCR in normal metaphase spreads by reverse fluorescence in situ hybridization. Whereas DNA repair sites in normal human cells are evenly distributed through the genome, TCR is highly localized at specific chromosomal domains. Particularly, clusters of TCR sites were identified at early-replicating gene-rich bands and telomeric regions of several chromosomes. High gene-density chromosomes such as chromosome 19 and the GC-rich domains of several chromosomes (T bands) are preferential locations of TCR. Our results demonstrate that the intragenomic localization of TCR resembles the uneven distribution of the human transcriptome, CpG islands, and hyperacetylated histones, enforcing the basic link between DNA repair, transcription, and nuclear organization in a complex genome.
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PMID:Clusters of transcription-coupled repair in the human genome. 1214 66

TRF2 is a telomere-binding protein that has a role in telomere protection. We generated mice that overexpress TRF2 in the skin. These mice had a severe phenotype in the skin in response to light, consisting of premature skin deterioration, hyperpigmentation and increased skin cancer, which resembles the human syndrome xeroderma pigmentosum. Keratinocytes from these mice were hypersensitive to ultraviolet irradiation and DNA crosslinking agents. The skin cells of these mice had marked telomere shortening, loss of the telomeric G-strand overhang and increased chromosomal instability. Telomere loss in these mice was mediated by XPF, a structure-specific nuclease involved in ultraviolet-induced damage repair and mutated in individuals with xeroderma pigmentosum. These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging. Finally, we show that a number of human skin tumors have increased expression of TRF2, further highlighting a role for TRF2 in skin cancer.
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PMID:XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. 1614 33

Two recent articles suggest new roles for the TERF2-XPF complex (a.k.a. TRF2-XPF) in the recognition/repair of DNA damage at non-telomeric chromosomal locations (i.e. "Caught in the Middle"). These new roles for proteins typically ascribed functions at the ends of chromosomes are proposed to be very early events of DNA damage response (i.e. Beginnings from the End). Our previous understanding of a role for the TERF2-XPF complex in the maintenance of chromosome stability included the preservation of telomere length by "suppression" of the recognition of chromosome ends as breaks. One recent paper demonstrates that TERF2 also functions at non-telomeric sites of DNA damage, and does so prior to initiation of the ATM signaling cascade. A second paper goes on to demonstrate that overexpression of TERF2 produces mouse phenotypes similar to those associated with xeroderma pigmentosum, such as cellular hypersensitivity to UV radiation and DNA crosslinking agents, and telomere shortening and chromosome instability in response to DNA damage. Moreover, data are presented illustrating that these abnormal responses are not seen in an XPF(-/-) background, consistent with a dependency on XPF. Interestingly, both manuscripts focus on events that transpire in response to exogenous DNA damage. Here, we review these exciting findings that suggest new roles for the TERF2-XPF complex and point out several questions that remain to be addressed.
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PMID:TERF2-XPF: caught in the middle; beginnings from the end. 1676 4

XPG is a structure-specific endonuclease required for nucleotide excision repair (NER). XPG incision defects result in the cancer-prone syndrome xeroderma pigmentosum, whereas truncating mutations of XPG cause the severe postnatal progeroid developmental disorder Cockayne syndrome. We show that XPG interacts directly with WRN protein, which is defective in the premature aging disorder Werner syndrome, and that the two proteins undergo similar subnuclear redistribution in S phase and colocalize in nuclear foci. The co-localization was observed in mid- to late S phase, when WRN moves from nucleoli to nuclear foci that have been shown to contain both protein markers of stalled replication forks and telomeric proteins. We mapped the interaction between XPG and WRN to the C-terminal domains of each, and show that interaction with the C-terminal domain of XPG strongly stimulates WRN helicase activity. WRN also possesses a competing DNA single-strand annealing activity that, combined with unwinding, has been shown to coordinate regression of model replication forks to form Holliday junction/chicken foot intermediate structures. We tested whether XPG stimulated WRN annealing activity, and found that XPG itself has intrinsic strand annealing activity that requires the unstructured R- and C-terminal domains but not the conserved catalytic core or endonuclease activity. Annealing by XPG is cooperative, rather than additive, with WRN annealing. Taken together, our results suggest a novel function for XPG in S phase that is, at least in part, performed coordinately with WRN, and which may contribute to the severity of the phenotypes that occur upon loss of XPG.
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PMID:The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome. 2191 2

The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein functions in latently infected cells as an essential participant in KSHV genome replication and as a driver of dysregulated cell growth. To identify novel LANA protein-cell protein interactions that could contribute to these activities, we performed a proteomic screen in which purified, adenovirus-expressed Flag-LANA protein was incubated with an array displaying 4,192 nonredundant human proteins. Sixty-one interacting cell proteins were consistently detected. LANA interactions with high-mobility group AT-hook 1 (HMGA1), HMGB1, telomeric repeat binding factor 1 (TRF1), xeroderma pigmentosum complementation group A (XPA), pygopus homolog 2 (PYGO2), protein phosphatase 2A (PP2A)B subunit, Tat-interactive protein 60 (TIP60), replication protein A1 (RPA1), and RPA2 proteins were confirmed in coimmunoprecipitation assays. LANA-associated TIP60 retained acetyltransferase activity and, unlike human papillomavirus E6 and HIV-1 TAT proteins, LANA did not reduce TIP60 stability. The LANA-bound PP2A B subunit was associated with the PP2A A subunit but not the catalytic C subunit, suggesting a disruption of PP2A phosphatase activity. This is reminiscent of the role of simian virus 40 (SV40) small t antigen. Chromatin immunoprecipitation (ChIP) assays showed binding of RPA1 and RPA2 to the KSHV terminal repeats. Interestingly, LANA expression ablated RPA1 and RPA2 binding to the cell telomeric repeats. In U2OS cells that rely on the alternative mechanism for telomere maintenance, LANA expression had minimal effect on telomere length. However, LANA expression in telomerase immortalized endothelial cells resulted in telomere shortening. In KSHV-infected cells, telomere shortening may be one more mechanism by which LANA contributes to the development of malignancy.
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PMID:A protein array screen for Kaposi's sarcoma-associated herpesvirus LANA interactors links LANA to TIP60, PP2A activity, and telomere shortening. 2237 92