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: 37.91). 08/2005; 5(7):564-73. DOI: 10.1038/nrc1652
Source: PubMed

ABSTRACT 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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    • "It is characterized by an extreme sun sensitivity especially to Ultra Violet Radiation (UVR) that induces cutaneous and mucous membranes cancers of the eyes and mouth [1]. XP is the archetype of an expanding family of Nucleotide Excision Repair (NER) diseases where XP cells were found to have defects in seven of the NER pathway proteins (XPA to XPG) [2]. "
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    ABSTRACT: Xeroderma Pigmentosum (XP) is a rare recessive autosomal cancer prone disease, characterized by UV hypersensitivity and early appearance of cutaneous and ocular malignancies. We investigated four unrelated patients suspected to be XP-C. To confirm linkage to XPC gene, genotyping and direct sequencing of XPC gene were performed. Pathogenic effect of novel mutations was confirmed by reverse Transciptase PCR. Mutation screening revealed the presence of two novel mutations g.18246G>A and g.18810G>T in the XPC gene (NG_011763.1). The first is present in one patient XP50NEF, but the second is present in three unrelated patients (XP16KEB, XP28SFA, and XP45GB). These 3 patients are from three different cities of Southern Tunisia and bear the same haplotype, suggesting a founder effect. Reverse Transciptase PCR revealed the absence of the XPC mRNA. In Tunisia, as observed in an other severe genodermatosis, the mutational spectrum of XP-C group seems to be homogeneous with some clusters of heterogeneity that should be taken into account to improve molecular diagnosis of this disease.
    07/2013; 2013:316286. DOI:10.1155/2013/316286
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    • "In the hereditary cancer syndrome Xeroderma pigmentosum , loss of NER genes induces skin cancer whose genome is characterized by high mutation rates at pyrimidine dimers [3]. However, most of the tumors do not show nucleotide instability, but rather they are characterized by the presence of gross chromosomal numerical and structural changes, which is referred as aneuploidy [2]. "
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    • "DNA polymerase eta (PolH), a member of the Y-family DNA polymerases, is originally identified as an enzyme with the ability to bypass translesion DNA synthesis (TLS) across ultraviolet (UV)induced pyrimidine dimers [1]. The UV light is the major carcinogen involved in the etiology of skin cancer [2]. In humans, the defect in the PolH gene results in xeroderma pigmentosum variant syndrome (XPV) [1] [3]. "
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    ABSTRACT: DNA polymerase eta (PolH), the product of the xeroderma pigmentosum variant (XPV) gene and a Y-family DNA polymerase, plays a pivotal role in translesion DNA synthesis. Loss of PolH leads to early onset of malignant skin cancer in XPV patients and increases UV-induced carcinogenesis. Thus, the pathways by which PolH expression and activity are controlled may be explored as a strategy to prevent UV-induced cancer. In this study, we found that Mdm2, a RING finger E3 ligase, promotes PolH degradation. Specifically, we showed that knockdown of Mdm2 increases PolH expression in both p53-proficient and -deficient cells. In addition, we showed that UV-induced PolH degradation is attenuated by Mdm2 knockdown. In contrast, ectopically expression of Mdm2 decreases PolH expression, which can be abrogated by the proteasome inhibitor MG132. Moreover, we showed that Mdm2 physically associates with PolH and promotes PolH polyubiquitination in vivo and in vitro. Finally, we showed that knockdown of Mdm2 increases the formation of PolH replication foci and decreases the sensitivity of cells to UV-induced lesions in a PolH-dependent manner. Taken together, we uncovered that Mdm2 serves as an E3 ligase for PolH polyubiquitination and proteasomal degradation in cells under the basal condition and in response to UV irradiation.
    DNA repair 11/2011; 11(2):177-84. DOI:10.1016/j.dnarep.2011.10.017 · 3.36 Impact Factor
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