Investigation of XPD, miR-145 and miR-770 expression in patients with end-stage renal disease.

BACKGROUND: The effective maintenance of genome integrity and fidelity is vital for the normal function of our tissues and organs, and the prevention of diseases. DNA repair pathways maintain genome stability, and the adequacy of genes acting in these pathways is essential for disease suppression and direct treatment responses. Chronic kidney disease is characterized by high levels of genomic damage. In this study, we examined the expression levels of the xeroderma pigmentosum group D (XPD) gene, which plays a role in the nucleotide excision repair (NER) repair mechanism, and the expression levels of miR-145 and miR-770 genes, which play a role in the regulation of the expression of the XPD gene, in hemodialysis patients with (n = 42) and without malignancy (n = 9) in pre- and post-dialysis conditions. We also evaluated these values with the clinical findings of the patients. METHODS & RESULTS: Gene expression analysis was performed by real-time polymerase chain reaction (qRT-PCR). Compared to the individuals with normal kidney function (2.06 ± 0.32), the XPD gene expression was lower in the pre-dialysis condition both in hemodialysis patients without cancer (1.24 ± 0.18; p = 0.02) and in hemodialysis patients with cancer (0.82 ± 0.114; p = 0.001). On the other hand, we found that miR-145 and miR-770 expression levels were high in both groups. We also found that expression levels were affected by dialysis processes. A statistically significant positive correlation was found between miR-145 and mir770 expression levels in the pre-dialysis group of patients with (r=-0.988. p = 0.0001) and without (r=-0.934. p = 0.0001) malignancy. CONCLUSIONS: Studies on DNA damage repair in the kidney will help develop strategies to protect kidney function against kidney diseases.

Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the ERCC4/XPF gene is essential for fetal development and most of previously reported ERCC4/XPF pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.

Whole Exome Sequencing of a Patient with a Milder Phenotype of Xeroderma Pigmentosum Group C.

A 17-year-old female Korean patient (XP115KO) was previously diagnosed with Xeroderma pigmentosum group C (XPC) by Direct Sanger sequencing, which revealed a homozygous nonsense mutation in the XPC gene (rs121965088: c.1735C > T, p.Arg579Ter). While rs121965088 is associated with a poor prognosis, our patient presented with a milder phenotype. Hence, we conducted whole-exome sequencing in the patient and her family members to detect coexisting mutations that may have resulted in a milder phenotype of rs121965088 through genetic interaction. Materials and Methods: the whole-exome sequencing analysis of samples obtained from the patient and her family members (father, mother, and brother) was performed. To identify the underlying genetic cause of XPC, the extracted DNA was analyzed using Agilent's SureSelect XT Human All Exon v5. The functional effects of the resultant variants were predicted using the SNPinfo web server, and structural changes in the XPC protein using the 3D protein modeling program SWISS-MODEL. Results: Eight biallelic variants, homozygous in the patient and heterozygous in her parents, were detected. Four were found in the XPC gene: one nonsense variant (rs121965088: c.1735C > T, p.Arg579Ter) and three silent variants (rs2227998: c.2061G > A, p. Arg687Arg; rs2279017: c.2251-6A > C, intron; rs2607775: c.-27G > C, 5'UTR). The remaining four variants were found in non-XP genes, including one frameshift variant [rs72452004 of olfactory receptor family 2 subfamily T member 35 (OR2T35)], three missense variants [rs202089462 of ALF transcription elongation factor 3 (AFF3), rs138027161 of TCR gamma alternate reading frame protein (TARP), and rs3750575 of annexin A7 (ANXA7)]. Conclusions: potential candidates for genetic interactions with rs121965088 were found. The rs2279017 and rs2607775 of XPC involved mutations in the intron region, which affected RNA splicing and protein translation. The genetic variants of AFF3, TARP, and ANXA7 are all frameshift or missense mutations, inevitably disturbing the translation and function of the resultant proteins. Further research on their functions in DNA repair pathways may reveal undiscovered cellular relationships within xeroderma pigmentosum.

Structural modeling and analyses of genetic variations in the human XPC nucleotide excision repair protein.

Xeroderma pigmentosum C (XPC) is a key initiator in the global genome nucleotide excision repair pathway in mammalian cells. Inherited mutations in the XPC gene can cause xeroderma pigmentosum (XP) cancer predisposition syndrome that dramatically increases the susceptibility to sunlight-induced cancers. Various genetic variants and mutations of the protein have been reported in cancer databases and literature. The current lack of a high-resolution 3-D structure of human XPC makes it difficult to assess the structural impact of the mutations/genetic variations. Using the available high-resolution crystal structure of its yeast ortholog, Rad4, we built a homology model of human XPC protein and compared it with a model generated by AlphaFold. The two models are largely consistent with each other in the structured domains. We have also assessed the degree of conservation for each residue using 966 sequences of XPC orthologs. Our structure- and sequence conservation-based assessments largely agree with the variant's impact on the protein's structural stability, computed by FoldX and SDM. Known XP missense mutations such as Y585C, W690S, and C771Y are consistently predicted to destabilize the protein's structure. Our analyses also reveal several highly conserved hydrophobic regions that are surface-exposed, which may indicate novel intermolecular interfaces that are yet to be characterized.Communicated by Ramaswamy H. Sarma.

A disease-associated XPA allele interferes with TFIIH binding and primarily affects transcription-coupled nucleotide excision repair.

XPA is a central scaffold protein that coordinates the assembly of repair complexes in the global genome (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER) subpathways. Inactivating mutations in XPA cause xeroderma pigmentosum (XP), which is characterized by extreme UV sensitivity and a highly elevated skin cancer risk. Here, we describe two Dutch siblings in their late forties carrying a homozygous H244R substitution in the C-terminus of XPA. They present with mild cutaneous manifestations of XP without skin cancer but suffer from marked neurological features, including cerebellar ataxia. We show that the mutant XPA protein has a severely weakened interaction with the transcription factor IIH (TFIIH) complex leading to an impaired association of the mutant XPA and the downstream endonuclease ERCC1-XPF with NER complexes. Despite these defects, the patient-derived fibroblasts and reconstituted knockout cells carrying the XPA-H244R substitution show intermediate UV sensitivity and considerable levels of residual GG-NER (~50%), in line with the intrinsic properties and activities of the purified protein. By contrast, XPA-H244R cells are exquisitely sensitive to transcription-blocking DNA damage, show no detectable recovery of transcription after UV irradiation, and display a severe deficiency in TC-NER-associated unscheduled DNA synthesis. Our characterization of a new case of XPA deficiency that interferes with TFIIH binding and primarily affects the transcription-coupled subpathway of nucleotide excision repair, provides an explanation of the dominant neurological features in these patients, and reveals a specific role for the C-terminus of XPA in TC-NER.

The role of UV-DDB in processing 8-oxoguanine during base excision repair.

Recent data from our laboratory has shown that the nucleotide excision repair (NER) proteins UV-damaged DNA-binding protein (UV-DDB), xeroderma pigmentosum group C (XPC), and xeroderma pigmentosum group A (XPA) play important roles in the processing of 8-oxoG. This review first discusses biochemical studies demonstrating how UV-DDB stimulates human 8-oxoG glycosylase (OGG1), MUTYH, and apurinic/apyrimidinic (AP) endonuclease (APE1) to increase their turnover at damage sites. We further discuss our single-molecule studies showing that UV-DDB associates with these proteins at abasic moieties on DNA damage arrays. Data from cell experiments are then described showing that UV-DDB interacts with OGG1 at sites of 8-oxoG. Finally, since many glycosylases are inhibited from working on damage in the context of chromatin, we present a working model of how UV-DDB may be the first responder to alter the structure of damage containing-nucleosomes to allow access by base excision repair (BER) enzymes.

Clinical, immunological, and genetic investigations in a rare association of type 1 diabetes with xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. Autoimmune diseases related to XP are rarely discussed in the literature. Type 1 diabetes (T1D) has been associated with other genodermatoses like Cockayne syndrome, but it has never been described in XP. In the present study, we report the rare occurrence of T1D in XP patients. Five XP patients belonging to 4 consanguineous families originating from different regions of Tunisia were investigated. Their ages ranged between 8 and 18 years. All the patients had a severe hypovitaminosis D. All the patients had positive GAD antibody levels, and 4 of them had familial history of other autoimmune diseases. The spectrum of XP was variable in all the patients, with dermatological and neurological symptoms, and the occurrence of some cancers. Various hypotheses have been proposed to explain this association, among of which we cite the role of immunomodulation and down-regulation of ATP-dependent DNA excision repair protein genes, implying that impaired DNA repair may contribute to the development of some autoimmune diseases. Vitamin D3 deficiency secondary to sun protective measures was found in all patients and thus may play a role in increasing T1D risk in these patients.

Involvement of Xeroderma Pigmentosum Complementation Group G (XPG) in epigenetic regulation of T-Helper (TH) cell differentiation during breast cancer.

TNFα and IFN-γ secreted by CD4+T-Helper (TH) cells have antitumor activity followed by polarisation of TH1 phenotype in response to IL-12 secreted by dendritic cells, inducing expression of XPG, Nucleotide-Excision Repair (NER) complex component, which is downregulated in breast cancer. Therefore, we investigated the involvement of XPG in TH-cell differentiation in breast cancer. XPG knock-out (KO) PBMC and TH1 polarised CD4+ TH-cells isolated from breast cancer and control subjects blood samples were used to observe mRNA expressions of associated genes, % enrichment of corresponding epigenetic markers, and m6A RNA methylation levels to study the molecular mechanisms involved. Assays to investigate Cytotoxic T Lymphocyte (CTL) activity after cross-checking extracellular secretion levels. Our XPGKO results indicated upregulation of TH2 and Treg, downregulation of TH1, and negligible change for TH17; reduced expression of genes associated with tumour suppression (TP53, BRCA1) and DNA repair (H2AFX, ATM) for breast cancer TH-cells. CTCF associated TH1 specific function, reduced %enrichment of XPG, CSA, and ERCC1, increased %enrichment of γH2A.X, and altered histone modifications (methylation, deacetylation) at the IFN-γ gene locus in XPGKO breast cancer TH1-cells. Increased m6A RNA methylation mediated by XPG leads to TH1 cell specificity, further inducing CTL activity by releasing extracellular IFG-γ, which activates CD8+ CTLs. This article explores the association of the vital NER protein, XPG with the epigenetic modifications behind TH1 cell differentiation, augmenting the expressions of TH1-network genes to evoke protective immunity in breast cancer.

A stable XPG protein is required for proper ribosome biogenesis: Insights on the phenotype of combinate Xeroderma Pigmentosum/Cockayne Syndrome patients.

Nucleotide Excision Repair is one of the five DNA repair systems. More than 30 proteins are involved in this process, including the seven XP proteins. When mutated, the genes coding for these proteins are provoking the rare disease Xeroderma Pigmentosum, which causes cutaneous defects and a high prevalence of skin cancers in patients. The CSA and CSB proteins are also involved in Nucleotide Excision Repair, and their mutation leads to Cockayne Syndrome, another rare disease, causing dwarfism, neurodegeneration, and ultimately early death, but without high skin cancer incidence. Some mutations of ERCC5, the gene coding for XPG, may give rise to a combined Xeroderma Pigmentosum and Cockayne Syndrome. A defect in Nucleotide Excision Repair alone cannot explain all these phenotypes. XPG has been located in the nucleolus, where ribosome biogenesis happens. This energy-consuming process starts with the transcription of the ribosomal DNA in a long ribosomal RNA, the pre-rRNA 47S, by RNA Polymerase 1. 47S pre-rRNA undergoes several cleavages and modifications to form three mature products: the ribosomal RNAs 18S, 5.8S and 28S. In the cytoplasm, these three products will enter the ribosomes' composition, the producers of protein in our cells. Our work aimed to observe ribosome biogenesis in presence of an unstable XPG protein. By working on Xeroderma Pigmentosum/Cockayne Syndrome cell lines, meaning in the absence of XPG, we uncovered that the binding of UBF, as well as the number of unresolved R-loops, is increased along the ribosomal DNA gene body and flanking regions. Furthermore, ribosomal RNA maturation is impaired, with increased use of alternative pathways of maturation as well as an increase of immature precursors. These defective processes may explain the neurodegeneration observed when the XPG protein is heavily truncated, as ribosomal homeostasis and R-loops resolution are critical for proper neuronal development.

Adult-Onset Neurodegeneration in Nucleotide Excision Repair Disorders (NERDND ): Time to Move Beyond the Skin.

BACKGROUND: Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early-onset neurological degeneration. Adult-onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations. OBJECTIVE: The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs. METHODS: In-house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER-related genes. Clinical workup included in-depth neurological and dermatological assessments. RESULTS: We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult-onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage. CONCLUSIONS: We introduce NERDND as adult-onset neurodegeneration (ND ) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERDND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

XPA Enhances Temozolomide Resistance of Glioblastoma Cells by Promoting Nucleotide Excision Repair.

Glioblastoma is the most frequent, as well as aggressive kind of high-grade malignant glioma. Chemoresistance is posing a significant clinical barrier to the efficacy of temozolomide-based glioblastoma treatment. By suppressing xeroderma pigmentosum group A (XPA), a pivotal DNA damage recognition protein implicated in nucleotide excision repair (NER), we devised a novel method to enhance glioblastoma therapy and alleviate temozolomide resistance. On the basis of preliminary assessment, we found that XPA dramatically increased in glioblastoma compared with normal cells and contributed to temozolomide resistance. By constructing XPA stably knockdown cells, we illustrate that XPA protects glioma cells from temozolomide-triggered reproductive cell death, apoptosis, as well as DNA repair. Besides, XPA silencing remarkably enhances temozolomide efficacy in vivo. This study revealed a crucial function of XPA-dependent NER in the resistance of glioma cells to temozolomide.

Type I Interferons Enhance the Repair of Ultraviolet Radiation-Induced DNA Damage and Regulate Cutaneous Immune Suppression.

Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNß in the skin of C57BL/6 mice. IFNα and IFNß were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.

Xeroderma Pigmentosum C: A Valuable Tool to Decipher the Signaling Pathways in Skin Cancers.

Xeroderma pigmentosum (XP) is a rare autosomal genodermatosis that manifests clinically with pronounced sensitivity to ultraviolet (UV) radiation and the high probability of the occurrence of different skin cancer types in XP patients. XP is mainly caused by mutations in XP-genes that are involved in the nucleotide excision repair (NER) pathway that functions in the removal of bulky DNA adducts. Besides, the aggregation of DNA lesions is a life-threatening event that might be a key for developing various mutations facilitating cancer appearance. One of the key players of NER is XPC that senses helical distortions found in damaged DNA. The majority of XPC gene mutations are nonsense, and some are missense leading either to the loss of XPC protein or to the expression of a truncated nonfunctional version. Given that no cure is yet available, XPC patients should be completely protected and isolated from all types of UV radiations (UVR). Although it is still poorly understood, the characterization of the proteomic signature of an XPC mutant is essential to identify mediators that could be targeted to prevent cancer development in XPC patients. Unraveling this proteomic signature is fundamental to decipher the signaling pathways affected by the loss of XPC expression following exposure to UVB radiation. In this review, we will focus on the signaling pathways disrupted in skin cancer, pathways modulating NER's function, including XPC, to disclose signaling pathways associated with XPC loss and skin cancer occurrence.

Every protagonist has a sidekick: Structural aspects of human xeroderma pigmentosum-binding proteins in nucleotide excision repair.

The seven xeroderma pigmentosum proteins (XPps), XPA-XPG, coordinate the nucleotide excision repair (NER) pathway, promoting the excision of DNA lesions caused by exposition to ionizing radiation, majorly from ultraviolet light. Significant efforts are made to investigate NER since mutations in any of the seven XPps may cause the xeroderma pigmentosum and trichothiodystrophy diseases. However, these proteins collaborate with other pivotal players in all known NER steps to accurately exert their purposes. Therefore, in the old and ever-evolving field of DNA repair, it is imperative to reexamine and describe their structures to understand NER properly. This work provides an up-to-date review of the protein structural aspects of the closest partners that directly interact and influence XPps: RAD23B, CETN2, DDB1, RPA (RPA70, 32, and 14), p8 (GTF2H5), and ERCC1. Structurally and functionally vital domains, regions, and critical residues are reexamined, providing structural lessons and perspectives about these indispensable proteins in the NER and other DNA repair pathways. By gathering all data related to the major human xeroderma pigmentosum-interacting proteins, this review will aid newcomers on the subject and guide structural and functional future studies.

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities.

Nucleotide excision repair (NER) is the most versatile DNA repair pathway, which can remove diverse bulky DNA lesions destabilizing a DNA duplex. NER defects cause several autosomal recessive genetic disorders. Xeroderma pigmentosum (XP) is one of the NER-associated syndromes characterized by low efficiency of the removal of bulky DNA adducts generated by ultraviolet radiation. XP patients have extremely high ultraviolet-light sensitivity of sun-exposed tissues, often resulting in multiple skin and eye cancers. Some XP patients develop characteristic neurodegeneration that is believed to derive from their inability to repair neuronal DNA damaged by endogenous metabolites. A specific class of oxidatively induced DNA lesions, 8,5'-cyclopurine-2'-deoxynucleosides, is considered endogenous DNA lesions mainly responsible for neurological problems in XP. Growing evidence suggests that XP is accompanied by defective mitophagy, as in primary mitochondrial disorders. Moreover, NER pathway is absent in mitochondria, implying that the mitochondrial dysfunction is secondary to nuclear NER defects. In this review, we discuss the current understanding of the NER molecular mechanism and focuses on the NER linkage with the neurological degeneration in patients with XP. We also present recent research advances regarding NER involvement in oxidative DNA lesion repair. Finally, we highlight how mitochondrial dysfunction may be associated with XP.

Xeroderma pigmentosum A homolog from Hydra partially complements DNA repair defect in human XPA-deficient cells.

Nucleotide excision repair (NER) pathway is a DNA repair mechanism that rectifies a wide spectrum of DNA lesions. Xeroderma pigmentosum group of proteins (XPA through XPG) orchestrate the NER pathway in humans. We have earlier studied XPA homolog from Hydra (HyXPA) and found it to be similar to human XPA. Here, we examined if HyXPA can functionally complement human XPA-deficient cells and reduce their sensitivity to UV radiation. We found that HyXPA was able to partially rescue XPA-deficient human cells from UV by its binding to chromatin of UV-irradiated cells. However, HyXPA failed to bind replication protein A (RPA70), a key interacting partner of human XPA in NER pathway. This could be attributed to changes in certain amino acid residues that have occurred during evolution, leading to prevention of some interactions between Hydra and human proteins.

Ribosomal protein S3 associates with the TFIIH complex and positively regulates nucleotide excision repair.

In mammalian cells, the bulky DNA adducts caused by ultraviolet radiation are mainly repaired via the nucleotide excision repair (NER) pathway; some defects in this pathway lead to a genetic disorder known as xeroderma pigmentosum (XP). Ribosomal protein S3 (rpS3), a constituent of the 40S ribosomal subunit, is a multi-functional protein with various extra-ribosomal functions, including a role in the cellular stress response and DNA repair-related activities. We report that rpS3 associates with transcription factor IIH (TFIIH) via an interaction with the xeroderma pigmentosum complementation group D (XPD) protein and complements its function in the NER pathway. For optimal repair of UV-induced duplex DNA lesions, the strong helicase activity of the TFIIH complex is required for unwinding damaged DNA around the lesion. Here, we show that XP-D cells overexpressing rpS3 showed markedly increased resistance to UV radiation through XPD and rpS3 interaction. Additionally, the knockdown of rpS3 caused reduced NER efficiency in HeLa cells and the overexpression of rpS3 partially restored helicase activity of the TFIIH complex of XP-D cells in vitro. We also present data suggesting that rpS3 is involved in post-excision processing in NER, assisting TFIIH in expediting the repair process by increasing its turnover rate when DNA is damaged. We propose that rpS3 is an accessory protein of the NER pathway and its recruitment to the repair machinery augments repair efficiency upon UV damage by enhancing XPD helicase function and increasing its turnover rate.

The involvement of nucleotide excision repair proteins in the removal of oxidative DNA damage.

The six major mammalian DNA repair pathways were discovered as independent processes, each dedicated to remove specific types of lesions, but the past two decades have brought into focus the significant interplay between these pathways. In particular, several studies have demonstrated that certain proteins of the nucleotide excision repair (NER) and base excision repair (BER) pathways work in a cooperative manner in the removal of oxidative lesions. This review focuses on recent data showing how the NER proteins, XPA, XPC, XPG, CSA, CSB and UV-DDB, work to stimulate known glycosylases involved in the removal of certain forms of base damage resulting from oxidative processes, and also discusses how some oxidative lesions are probably directly repaired through NER. Finally, since many glycosylases are inhibited from working on damage in the context of chromatin, we detail how we believe UV-DDB may be the first responder in altering the structure of damage containing-nucleosomes, allowing access to BER enzymes.

Sunlight, Vitamin D, and Xeroderma Pigmentosum.

Sunlight, in particular UV-B radiation, is an important factor for endogenous vitamin D production as 80-90% of the required vitamin D needs to be photosynthesized in the skin. The active form of vitamin D, vitamin D3 or calcitriol, binds to the ligand-activated transcription factor vitamin D receptor (VDR) for genomic and non-genomic effects. Recently, calcitriol and analogs have been shown to have antiproliferative effects in mouse and human BCC and SCC cell lines in vitro. As UV radiation plays a critical role in the photosynthesis of vitamin D, stringent sun protection, as recommended for xeroderma pigmentosum (XP) patients, may impact their vitamin D levels.XP is a rare autosomal recessive disorder with a worldwide prevalence of 1 in 1,000,000. XP can be divided into seven different complementation groups: XP-A to XP-G. The complementation groups correspond with the underlying gene defect. Defects in these genes lead to a defective nucleotide excision repair (NER), which is necessary to remove UV-induced DNA damage such as the UV photoproducts cyclobutane pyrimidine dimers (CPD) and 6-4 pyrimidine-pyrimidone (6-4 PP) dimer. Additionally, a variant form with a mutation in the translational polymerase η gene (PolH), also called XP variant (XPV), exists. Patients with XPV show a defect in translesion synthesis. Due to their inability to repair UV-induced lesions, XP patients exhibit an increased risk for UV-induced nonmelanoma skin cancer (NMSC) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) as well as melanoma. Although no curative therapy for XP exists today, numerous options for the treatment and prophylaxis of skin cancer have become available.

A novel missense variant and multiexon deletion causing a delayed presentation of xeroderma pigmentosum, group C.

Pathogenic variants in the XPC complex subunit, DNA damage recognition, and repair factor (XPC) are the cause of xeroderma pigmentosum, group C (MIM: 278720). Xeroderma pigmentosum is an inherited condition characterized by hypersensitivity to ultraviolet (UV) irradiation and increased risk of skin cancer due to a defect in nucleotide excision repair (NER). Here we describe an individual with a novel missense variant and deletion of exons 14-15 in XPC presenting with a history of recurrent melanomas. The proband is a 39-yr-old female evaluated through the Mayo Clinic Department of Clinical Genomics. Prior to age 36, she had more than 60 skin biopsies that showed dysplastic nevi, many of which had atypia. At age 36 she presented with her first melanoma in situ, and since then has had more than 10 melanomas. The proband underwent research whole-exome sequencing (WES) through the Mayo Clinic's Center for Individualized Medicine and a novel heterozygous variant of uncertain significance (VUS) in XPC (c.1709T > G, p.Val570Gly) was identified. Clinical confirmation pursued via XPC gene sequencing and deletion/duplication analysis of XPC revealed a pathogenic heterozygous deletion of ∼1 kb within XPC, including exons 14 and 15. Research studies determined the alterations to be in trans Although variants in XPC generally result in early-onset skin cancer in childhood, the proband is atypical in that she did not present with her first melanoma until age 36. Review of the patient's clinical, pathological, and genetic findings points to a diagnosis of delayed presentation of xeroderma pigmentosum.