Cleaver JE.Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer 5:564-573

Auerback Melanoma Laboratory, Room N431, UCSF Cancer Center, University of California, 94143-0808, USA.
Nature reviews. Cancer (Impact Factor: 37.4). 08/2005; 5(7):564-73. DOI: 10.1038/nrc1652
Source: PubMed


Nucleotide-excision repair diseases exhibit cancer, complex developmental disorders and neurodegeneration. Cancer is the hallmark of xeroderma pigmentosum (XP), and neurodegeneration and developmental disorders are the hallmarks of Cockayne syndrome and trichothiodystrophy. A distinguishing feature is that the DNA-repair or DNA-replication deficiencies of XP involve most of the genome, whereas the defects in CS are confined to actively transcribed genes. Many of the proteins involved in repair are also components of dynamic multiprotein complexes, transcription factors, ubiquitylation cofactors and signal-transduction networks. Complex clinical phenotypes might therefore result from unanticipated effects on other genes and proteins.

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    • "Although many NER proteins have been identified and functionally characterized, new proteins that participate in these processes are continually being discovered67. The increasing complexity of the NER pathway consequently makes it difficult to ascertain the exact causal factor of NER deficiency that leads to mutation accumulation and cancer8910. "
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    ABSTRACT: Nucleotide excision repair (NER) excises bulky DNA lesions induced by mutagens and carcinogens. The repair process includes recognition of DNA damage, excision of a short patch of nucleotides containing the damaged base, re-synthesis of a new DNA strand and ligation of the nicks to restore the sequence integrity. Mutation or aberrant transcription of NER genes reduces repair efficiency and results in the accumulation of mutations that is associated with the development of cancer. Here we present a rapid, sensitive and quantitative assay to measure NER activity in human cells, which we term the Oligonucleotide Retrieval Assay (ORA). We used oligonucleotide constructs containing the UV-damaged adduct, cyclobutane pyrimidine dimer (CPD), to transfect human cells, and retrieved the oligonucleotides for quantification of the repaired, CPD-free DNA by real-time quantitative PCR. We demonstrate that ORA can quantify the extent of NER in diverse cell types, including immortalized, primary and stem-like cells.
    Full-text · Article · May 2014 · Scientific Reports
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    • "These steps include unwinding of DNA, excision of a single strand fragment of 24–32 nucleotides containing the lesion, and gap filling using the undamaged strand as template [20]–[22]. Mutations in seven well characterized NER genes (XPA to XPG), including DDB2 (XPE), result in Xeroderma Pigmentosum (XP), a recessive inherited syndrome characterized by heightened UV-sensitivity, neurological abnormalities, and an increased susceptibility to develop skin cancers [23], [24]. "
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    ABSTRACT: Because cells are constantly subjected to DNA damaging insults, DNA repair pathways are critical for genome integrity [1]. DNA damage recognition protein complexes (DRCs) recognize DNA damage and initiate DNA repair. The DNA-Damage Binding protein 2 (DDB2) complex is a DRC that initiates nucleotide excision repair (NER) of DNA damage caused by ultraviolet light (UV) [2]-[4]. Using a purified DDB2 DRC, we created a probe ("DDB2 proteo-probe") that hybridizes to nuclei of cells irradiated with UV and not to cells exposed to other genotoxins. The DDB2 proteo-probe recognized UV-irradiated DNA in classical laboratory assays, including cyto- and histo-chemistry, flow cytometry, and slot-blotting. When immobilized, the proteo-probe also bound soluble UV-irradiated DNA in ELISA-like and DNA pull-down assays. In vitro, the DDB2 proteo-probe preferentially bound 6-4-photoproducts [(6-4)PPs] rather than cyclobutane pyrimidine dimers (CPDs). We followed UV-damage repair by cyto-chemistry in cells fixed at different time after UV irradiation, using either the DDB2 proteo-probe or antibodies against CPDs, or (6-4)PPs. The signals obtained with the DDB2 proteo-probe and with the antibody against (6-4)PPs decreased in a nearly identical manner. Since (6-4)PPs are repaired only by nucleotide excision repair (NER), our results strongly suggest the DDB2 proteo-probe hybridizes to DNA containing (6-4)PPs and allows monitoring of their removal during NER. We discuss the general use of purified DRCs as probes, in lieu of antibodies, to recognize and monitor DNA damage and repair.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "The very significant overlap of transcripts differentially regulated in ERCC3 (XPB) deficient cells after UVR was the most striking of the gene sets overlapping with the transcripts altered in response to cisplatin in the melanoma cell lines. The previously reported absence of XPB induction [9] and the highly significant overlap with transcripts altered in XPB deficient fibroblasts after UVR is highly suggestive of melanoma cells having a very limited NER capacity of somewhere between 3% and 7% of normal as reported in XPB deficient fibroblasts [35]. Given that one of the key clinical features of individuals with mutations in the XPB gene is UVR sensitivity and an increase in UV-induced melanomas [35], the role of this gene in melanomagenesis and cisplatin resistance in the general population requires further investigation. "
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    ABSTRACT: Nucleotide excision repair (NER) orchestrates the repair of helix distorting DNA damage, induced by both ultraviolet radiation (UVR) and cisplatin. There is evidence that the global genome repair (GGR) arm of NER is dysfunctional in melanoma and it is known to have limited induction in melanoma cell lines after cisplatin treatment. The aims of this study were to examine mRNA transcript levels of regulators of GGR and to investigate the downstream effect on global transcript expression in melanoma cell lines after cisplatin treatment and in melanoma tumours. The GGR regulators, BRCA1 and PCNA, were induced in melanocytes after cisplatin, but not in melanoma cell lines. Transcripts associated with BRCA1, BRCA2, ATM and CHEK2 showed altered expression in melanoma cell lines after cisplatin treatment. In melanoma tumour tissue BRCA1 transcript expression correlated with poor survival and XPB expression correlated with solar elastosis levels. Taken together, these findings provide evidence of the mechanisms underlying NER deficiency in melanoma.
    Full-text · Article · Aug 2013 · PLoS ONE
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