The xeroderma pigmentosum group C gene leads to selective repair of cyclobutane pyrimidine dimers rather than 6-4 photoproducts

Emmert, Steffen; Kobayashi, Nobuhiko; Khan, Sikandar G.; Kraemer, Kenneth H.

doi:10.1073/pnas.040559697

Cited by 79 publications

(65 citation statements)

References 47 publications

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“…The XPC protein recognizes a variety of bulky DNA damages including UV-caused cyclobutane pyrimidine dimers and cisplatin-generated interstrand crosslinks (ICL) [9][10][11][12][13][14][15][16]. The XPC protein binds tightly with an HR23B protein to form a stable XPC-HR23B complex [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

The involvement of XPC protein in the cisplatin DNA damaging treatment-mediated cellular response

et al. 2004

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Recognition of DNA damage is a critical step for DNA damage-mediated cellular response. XPC is an important DNA damage recognition protein involved in nucleotide excision repair (NER). We have studied the XPC protein in cisplatin DNA damaging treatment-mediated cellular response. Comparison of the microarray data from both normal and XPCdefective human fibroblasts identified 861 XPC-responsive genes in the cisplatin treatment (with minimum fold change>1.5).The cell cycle and cell proliferation-related genes are the most affected genes by the XPC defect in the treatment. Many other cellular function genes, especially the DNA repair and signal transduction-related genes, were also affected by the XPC defect in the treatment. To validate the microarray data, the transcription levels of some microarray-identified genes were also determined by an RT-PCR based real time PCR assay. The real time PCR results are consistent with the microarray data for most of the tested genes, indicating the reliability of the microarray data. To further validate the microarray data, the cisplatin treatment-mediated caspase-3 activation was also determined. The Western blot hybridization results indicate that the XPC defect greatly attenuates the cisplatin treatment-mediated Caspase-3 activation. We elucidated the role of p53 protein in the XPC protein DNA damage recognition-mediated signaling process. The XPC defect reduces the cisplatin treatment-mediated p53 response. These results suggest that the XPC protein plays an important role in the cisplatin treatment-mediated cellular response. It may also suggest a possible mechanism of cancer cell drug resistance.

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Section: Introductionmentioning

confidence: 99%

The involvement of XPC protein in the cisplatin DNA damaging treatment-mediated cellular response

et al. 2004

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“…They may have different affinities for each type of UV damage and might need DDB2 for recruitment to CPD, whereas XPC efficiently recognizes 6-4PPs (4,37). Nevertheless, Emmert et al (38) reported that a truncated XPC protein leads to repair of CPDs but not of 6-4PPs. Our data indicate that the ability to repair both types of DNA damage may depend on the amount of available XPC protein.…”

Section: Discussionmentioning

confidence: 99%

Repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons

Kuschal

DiGiovanna

Khan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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About 12% of human genetic disorders involve premature termination codons (PTCs). Aminoglycoside antibiotics have been proposed for restoring full-length proteins by readthrough of PTC. To assess the efficiency of readthrough, we selected homozygous and compound heterozygous skin fibroblasts from xeroderma pigmentosum (XP) patients with different PTCs in the XPC DNA repair gene. XP patients have a nucleotide excision repair defect and a 10,000-fold increased risk of UV-induced skin cancer. In six of eight PTC-containing XP-C cells, treatment with Geneticin and gentamicin resulted in (i) stabilized XPC-mRNA, which would have been degraded by nonsense-mediated decay; (ii) increased expression of XPC protein that localized to UV-damaged sites; (iii) recruitment of XPB and XPD proteins to UV DNA damage sites; and (iv) increased repair of 6-4 photoproducts and cyclobutane pyrimidine dimers. Expression of PTC in a transfected vector revealed that readthrough depends on the PTC sequence and its location within the gene. This sensitive DNA repair assay system demonstrates the complexity of response to PTC readthrough inducers. The efficiency of aminoglycoside-mediated readthrough depends on the type and copy number of PTC, the downstream 4+ nucleotide, and the location within the exon. Treatment with small-molecule nonaminoglycoside compounds (PTC124, BZ16, or RTC14) resulted in similarly increased XPC mRNA expression and photoproduct removal with less toxicity than with the aminoglycosides. Characterizing PTC structure and parameters governing effective PTC readthrough may provide a unique prophylactic therapy for skin cancer prevention in XP-C patients.readthrough compounds | UV radiation

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“…Protein extraction and Western-blot analysis with chemiluminescent detection were as described by Emmert et al (2000). The following antibodies and dilution factors were used: mouse anti-XPC (1:3000), mouse-actin (H-196, Santa Cruz, Santa Cruz, CA, USA, 1:50 000) and antimouse peroxidase-conjugated immunoglobulin G (IgG-HRP, Santa Cruz, 1:5000).…”

Section: Rnai and Bap Treatmentmentioning

confidence: 99%

Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers

Chang

Cheng

et al. 2007

Oncogene

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Reduced DNA repair capability is associated with developing lung cancer, especially in nonsmokers. XPC participates in the initial recognition of DNA damage during the DNA nucleotide excision repair process. We hypothesize that inactivation of XPC by promoter hypermethylation may play an important role in the reduction of DNA repair capability to cause p53 mutation during lung carcinogenesis. In this report we demonstrate that hypermethylation of 17 CpG islands between À175 and À1 of the XPC promoter correlates very well with XPC expression levels in eight lung cancer cell lines. When cells with hypermethylated XPC promoters were treated with the demethylating agent 5-aza-2 0 -deoxycytidine, XPC expression was de-repressed. Interestingly, XPC hypermethylation was found in 4 of 5 (80%) lung cancer cell lines harbored p53 mutation, but not observed in two lung cancer cells which had a wild-type p53 gene. Among the analysis of the hypermethylation status of 158 lung tumors, XPC hypermethylation is more common in nonsmokers (39 of 94, 41%) than in smokers (14 of 64, 22%; P ¼ 0.010). Additionally, XPC hypermethylation is more often with G-T or G-C mutations in the p53 gene. To verify whether XPC inactivation is involved in the occurrence of p53 mutation, XPC gene of A549 cells was knockdown by a small interference RNA and then XPC-inactivated cells were treated with benzo[a]pynrene for different passages. Surprisingly, G-T mutation in p53 gene at codon 215 was indeed detected in XPCinactivated A549 cells of passages 15 and confirmed by loss of transcription activity of mdm2. These results show that hypermethylation of the XPC promoter may play a crucial role in XPC inactivation, which may partly contribute to the occurrence of p53 mutations during lung tumorigenesis, especially nonsmokers.

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The xeroderma pigmentosum group C gene leads to selective repair of cyclobutane pyrimidine dimers rather than 6-4 photoproducts

Cited by 79 publications

References 47 publications

The involvement of XPC protein in the cisplatin DNA damaging treatment-mediated cellular response

The involvement of XPC protein in the cisplatin DNA damaging treatment-mediated cellular response

Repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons

Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers

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