In eukaryotes, XERODERMA PIGMENTOSUM GROUP D (XPD) is an integral subunit of the DNA repair/transcription complex TFIIH. In animals, XPD has been implicated in TFIIH-independent complexes regulating cell division, which, however, remains poorly understood in plants. Here, we identified XPD as a novel regulator of stomatal development in Arabidopsis. Its loss-of-function mutants exhibited increased stomatal precursor cells and formed stomatal clusters. Genetic analysis showed that XPD functions upstream of SPEECHLESS (SPCH) to control stomatal lineage entry, coordinates with MUTE to regulate meristemoid division and works together with FLP and FAMA to restrict GMC division. In a search of XPD interactors, we identified CDKA;1, which serves as both an essential cyclin-dependent kinase and a key SPCH activator. Consistently, xpd mutants exhibited enhanced stomatal lineage cell divisions and elevated SPCH protein levels. Furthermore, XPD acts upstream of CDKA;1, as expression of the dominant-negative CDKA;1.N146 allele significantly suppressed the excessive cell division and stomatal development defects in xpd plants. Our data highlight the precise regulation of stomatal development by XPD, expanding its critical TFIIH-independent roles in plant cell division and fate specification.

Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder caused by defective nucleotide excision repair. Although dermatological features are well characterized, data on ocular manifestations and associated genotypes in Indian populations remain limited. This study aimed to delineate the ocular phenotype and underlying genetic variants in Indian patients with XP and compare them with global data. Retrospective review of 23 patients with genetically confirmed XP was conducted. Variant pathogenicity was assessed using in silico tools. Logistic regression analysis and Generalized Estimating Equations model with a logit link function was used to evaluate any potential associations between clinical genetic parameters with the occurrence of ocular surface neoplasia (OSN). The cohort (median age: 24 years; male: female = 15:8) had a high consanguinity rate (69.6%). All patients reported of photophobia and visual impairment. Ocular surface dryness was also a notable complaint in 17%. Frequent ocular findings included conjunctival abnormalities (97%), corneal involvement (80%), and eyelid changes (70%). OSN or lid/adnexal tumors together were observed in 37% of eyes. Whole exome sequencing identified 18 pathogenic/likely pathogenic variants-15 in XP-C and 3 in DDB2 (XP-E), including 12 novel variants. There was a statistically significant increased risk of OSN in XP-E subtype compared with XP-C subtype. XP-C was the predominant subtype, followed by XP-E in patients with XP with ocular involvement. XP-E subtype has been reported for the first time in Indian data in this study. Most variants were frameshift or stop gain. The patients with XP-E subtype may be more at risk of OSN development. These findings underscore the importance of routine ocular surveillance and genetic testing in XP.

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are diseases provoked by mutations in multifunctional proteins that are involved in DNA repair. DNA-repair deficiency explains the high cancer incidence of XP, whereas cancer-free CS, characterized by growth retardation, neurological degeneration, and premature aging does not present as a classical DNA-repair deficiency disorder. Here, we compared a severe combined XP/CS case provoked by XPG-mutation with an XP "only" patient cell line caused by mutation in the same XPG gene to carve out the pathogenic cellular disturbances that provoke CS. We identified RNA polymerase I transcription and rRNA maturation defects, a highly phosphorylated eukaryotic initiation factor 2 alpha (eIF2alpha), and a shift from cap- to internal ribosomal entry site (IRES) translation, indicating an activated integrated stress response in CS. Disturbances in ribosomal biogenesis and translational control might thus contribute to the development of CS.

Xeroderma pigmentosum (XP) is a rare DNA damage repair disorder. Seven distinct complementation groups and XP-variant form have been identified; however, limited literature exists on the genotype-phenotype correlation in XP. This study explores XP manifestations associated with variants in patients from Türkiye. A multicentric investigation involved 69 XP patients from 52 unrelated families across 12 centers in Türkiye. Clinical examinations and genetic testing were conducted to assess the correlation between variants and disease characteristics. XP-C group was the most prevalent group (n=38, 55%), followed by XP-V (n=15, 21.7%), XP-E (n=8, 11.6%), XP-D (n=4, 5.8%), XP-A (n=3, 4.3%), and XP-G (n=1, 1.4%). No XP-B and XP-F groups were identified. The median diagnosis age was 8.5 years, though this varied significantly among complementation groups, with diagnoses in XP-D and XP-V occurring later. Genetic analyses revealed 30 novel variants, including one in a patient with XP/Cockayne syndrome complex. Despite XP-D's link to neurological degeneration, none showed neuropathy, while three XP-E patients exhibited neurological involvement. Notably, 26% (n=18) of patients reported no consanguinity, yet a significant proportion (11/18) had distant family members with XP. We observed unique clinical patterns in XP patients and diversity among complementation groups in Türkiye. Future investigations should focus on functional characterization of the novel variants, preferably through assays like unscheduled DNA synthesis (UDS), to determine their potential impact on DNA repair mechanisms and their implications for improved patient care.

Xeroderma Pigmentosum group C (XP-C) is an autosomal recessive disorder caused by mutations in the XPC gene, leading to defective nucleotide excision repair. This defect leads to genomic instability and a profound cancer predisposition. To model this disease, we generated induced pluripotent stem cells (iPSCs) from an XP-C patient carrying a novel homozygous nonsense mutation in the XPC gene (c.1830C>A). The resulting iPSCs demonstrated typical pluripotent characteristics, including expression of key markers and trilineage differentiation capability. However, genomic assessment revealed progressive karyotypic instability during extended culture. While initial whole-genome sequencing detected no major chromosomal abnormalities, subsequent G-banding analysis identified acquired trisomy 12 in two lines (CL12 and CL27) and a derivative X chromosome in a third line (CL30). These abnormalities were absent in early-passage analyses, indicating that they were acquired and selected for during extended culture. The acquisition of a derivative X chromosome in CL30, alongside recurrent trisomy 12, represents a unique cytogenetic signature likely attributable to the underlying XPC defect. We hypothesize that the loss of GG-NER creates a permissive genomic environment, accelerating the accumulation of DNA damage and chromosomal missegregation under replicative stress. This temporal divergence in genomic integrity highlights how culture pressures drive chromosomal evolution in XP-C iPSCs independently of initial reprogramming. Our findings emphasize that XP-C iPSCs require continuous genomic surveillance and provide a model for investigating how DNA repair deficiencies interact with in vitro culture stress.

CRISPR/Cas9-mediated editing of XPA in induced pluripotent stem cells: A model for investigating Xeroderma Pigmentosum and NER dysfunction.

461 Identification of a Novel Pathogenic XPC:c.2420+1G>C Variant in a Patient with Xeroderma Pigmentosum

Exploring the interaction between nucleotide excision repair pathways and Huntington disease: Implications for neurodegeneration and phenotypic overlap.

XPD is an evolutionarily conserved protein critical for DNA repair, transcription, cell cycle, and chromosome segregation. XPD mutations result in complex genetic diseases, including xeroderma pigmentosum (XP). XPD is also implicated in protecting cells from oxidative stress but has not been linked to specific metabolic gene functions. Here, we report an intriguing genetic interaction between Drosophila Xpd and the scheggia (sea) gene encoding the mitochondrial citrate transporter. We show that the reduced eye size by Xpd RNAi in Drosophila is partially restored by the knockdown of sea. sea RNAi suppresses ectopic cell death and DNA damages resulting from Xpd knockdown. To test whether this negative relationship between Xpd and sea can be recapitulated in human cells, we examined the effects of CTPI-2, an inhibitor of the human citrate transporter SLC25A1, on the survival of XPD mutant cells (HD2) carrying the R683W point mutation (XPDR683W). CTPI-2 reduced the survival of UV-irradiated HeLa cells used as control. In contrast, the same level of CTPI-2 increased the viability of HD2 mutant cells exposed to a wide range of UV doses. In response to UV irradiation, HD2 cells are defective in unscheduled DNA synthesis (UDS). CTPI-2 increased the UDS response in HD2 cells. These data indicate that UV-induced DNA damage and lethality of human XPD mutant cells can be suppressed by inhibiting SLC25A1 by CTPI-2, consistent with the genetic interaction between Xpd and sea in Drosophila. This work suggests that XPD is antagonistically related to SLC25A1, and the citrate transporter may be a therapeutic target for alleviating XP syndrome.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-26976-0.

437 A New Frontier for Xeroderma Pigmentosum Research: Xenopus Embryos as Dynamic In Vivo Models of DNA Damage and Pigmentary Dysregulation

ABSTRACT Spironolactone (SP), a clinically used aldosterone antagonist, has been explored as an anti-HIV agent in models of HIV-1 latency for inducing transcriptional silencing of the viral reservoir. SP promotes the degradation of xeroderma pigmentosum group B (XPB) protein, a crucial component of transcription factor II H (TFIIH) required for RNA polymerase II transcriptional initiation. This study evaluated the impact of a long-acting formulation of SP on HIV replication within the context of antiretroviral therapy (ART) in the humanized mice model of HIV infection. The findings demonstrate that adding SP to ART accelerates viral decline and reduces expression of inflammation-related genes in human immune cells – genes often upregulated in chronic viral infections. Although SP treatment did not alter levels of cell-associated viral DNA, it led to a significant 4.4-fold decrease in systemic cell-associated viral RNA. This supports the role of XPB in HIV transcriptional regulation and advocates for incorporating transcriptional inhibitors like SP into primary HIV therapy. Additionally, SP treatment diminished markers of immune activation and inflammation, critical factors contributing to morbidity and mortality in individuals with chronic HIV infection. These results highlight SP’s potential to enhance HIV treatment by mitigating key aspects of viral persistence and associated immune challenges.

XPD is a key nucleotide excision repair (NER) protein whose function is vital for genome integrity. During NER, XPD serves as a 5′−3′ single-strand DNA translocase that enables lesion scanning and verification in genomic DNA. Yet, its translocation mechanism is incompletely understood. Here we use molecular simulations and chain-of-replicas path optimization methods to model the ATP-driven translocation mechanisms of XPD and its bacterial homolog DinG, revealing all on-path metastable intermediates and corresponding kinetic rates. We identify the XPD(DinG) global domain motions that modulate the strength of DNA association at the opposing ends of the DNA-binding groove. During the ATP hydrolysis cycle, alternating weak and strong interactions at two defined groove constrictions enable DNA reptation and forward displacement of the ATPase. Moreover, we show that DNA- or ATP-binding residues directly involved in translocation are hotspots for genetic disease mutations. Thus, our findings shed light on the etiology of XPD-associated genetic syndromes.

The incidence of skin cancer has been steadily increasing worldwide with annual growth equal from 3 to 10% in recent years. Skin malignancies (MNs), with the exception of melanoma, are on the second place in the structure of oncological morbidity in the Russian Federation. Unfortunately, skin cancer is often diagnosed at late stages despite the fact that it is external tumor. Most probably, it is associated with insufficient oncological alertness of patients and healthcare professionals. The group of keratinocyte carcinomas also called non-melanoma skin cancer include basal cell carcinoma (basal cell skin cancer) and squamous cell carcinoma (squamous cell skin cancer). Basal cell skin cancer is the most common tumor accounting for up to 75% of all epithelial MNs. Squamous cell skin cancer is also fairly prevalent malignant epithelial tumor of the skin. The main factor of carcinomas occurrence is exposure to ultraviolet radiation. In addition to cumulative ultraviolet exposure other risk factors include chronic skin inflammation, chemical carcinogens, immunosupression (including HIV infection and drug-induced immunosupression after organs transplantation) and xeroderma pigmentosum. The review presents summarized data on epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment and prevention of skin carcinoma. It is important to note that the first specialists who meet such patients are general practitioners, cosmetologists and dermatologists, who are responsible for timely diagnosis and referral of these patients to an oncologist.

To explore the clinical presentation and genetic etiology of a case with Xeroderma pigmentosum in conjunct with basal cell carcinoma and melanoma. A male patient with Xeroderma pigmentosum treated at Xinxiang Central Hospital in October 2022 was selected as study subject. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing of his family members. This study was approved by the Ethics Committee of the hospital (Ethics No.: 2021-167). Magnetic resonance imaging showed that the patient has a solid soft tissue mass in the anterior and lower part of his right eyeball and a small nodule on the left nasal wing. Histopathological biopsy showed that the periocular tumor was basal cell carcinoma in conjunct with malignant melanoma, and the nasal wing tumor was basal cell carcinoma. WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the XPC gene, namely c.2391delT (p.F797Lfs*11) and IVS1+1G>A, which were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were rated as likely pathogenic (PVS1+PM2_Supporting+PM3) and pathogenic (PVS1+PM2_Supporting+PM3+PP5), respectively. The c.2391delT variant was unreported previously. Bioinformatic analysis suggests that it could significantly affect the tertiary structure of XPC protein. The c.2391delT(p.F797Lfs*11) and IVS1+1G>A compound heterozygous variants probably underlay the pathogenesis in this patient. The detection of the novel variant has enriched the mutational spectrum of the XPC gene.

CIC::DUX4 sarcoma (CDS) is a lethal cancer driven by a fusion between tumor suppressor Capicua (CIC) and pioneer transcription factor double homeobox 4 (DUX4). To develop an immunocompetent pre-clinical model of CDS, we previously generated three genetically engineered mouse models (GEMMs) of CDS with CIC::DUX4 regulated by loxP-STOP-loxP cassettes. However, all three models developed spontaneous tumors without Cre recombinase. Here, we established an innovative GEMM of CDS (dFLEx CDS) that employs a dual recombinase (Cre + FLPE) FLEx-switch design to activate CIC::DUX4 expression and initiate sarcomagenesis in a spatially and temporally-controlled manner. Because CIC::DUX4 drives sarcoma development by activating a distinct oncogenic transcriptional program, we performed a drug screen on human-derived CDS cell lines using a library of compounds that modulate transcriptional regulation. This screen identified Minnelide, an inhibitor of RNA polymerase II-mediated transcription, as a selective inhibitor of CDS. Mechanistically, Minnelide acted through xeroderma pigmentosum type B to alter phosphorylation of RPB1, the largest subunit of RNA polymerase II. Subsequently, RPB1 underwent degradation leading to apoptosis of CDS cells. Minnelide demonstrated in vivo efficacy in autochthonous dFLEx CDS GEMMs and in human CDS xenografts. As Minnelide has already been demonstrated to be safe in clinical trials with activity for adult cancers, these findings nominate Minnelide as a novel therapeutic option to test in CDS patients.

Defective mitophagy of CD4+T cells in ITP via NAD+/SIRT1 reduction

Xeroderma pigmentosum as a germline predisposition syndrome for haematological malignancies

Oral squamous cell carcinoma risk and magnitude of association in inherited cancer predisposition syndromes: evidence from a large real-world cohort.

Xeroderma pigmentosum complementation group C (XPC) is reported to play important roles in DNA integrity and genomic instability, however, the contribution of XPC to colorectal cancer (CRC) carcinogenesis is largely uncertain. Therefore, we aimed to examine the potential associations of XPC rs2228000 and rs2228001 genotypes and CRC susceptibility in a Taiwanese cohort. A total of 362 patients with CRC and non-cancer controls were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. The distribution of genotypes and alleles was assessed, and conformity to Hardy-Weinberg equilibrium was checked. Firstly, no statistically significant differences were observed in the genotypic frequencies of XPC rs2228000 and rs2228001 between patients with CRC and healthy controls (p for trend=0.5419 and 0.5005, respectively). Secondly, the allelic analyses revealed lack of associations with CRC risk regarding XPC rs2228000 T allele (odds ratio=0.89, 95% confidence interval=0.72-1.11, p=0.3446), and rs2228001 C allele (odds ratio=1.14, 95% confidence interval=0.92-1.41, p=0.2688). Interestingly, individuals carrying the CT or TT genotypes of XPC rs2228000 were prone to presenting metastatic behavior (p=0.0001). Moreover, individuals carrying the AC or CC genotypes of XPC rs2228001 were more likely to have larger tumor sizes (≥5 cm, p=0.0116), lymph node involvement (p=0.0014), advanced clinical stage (III-IV, p=0.0002), and metastasis (p=0.0002). Although the investigated XPC polymorphisms were not associated with CRC susceptibility, the rs2228000 and rs2228001 variant genotypes may serve as novel prognostic biomarkers. Further large-scale studies across diverse populations are recommended to validate these findings.

Clinical outcomes of 3D-total body photography and digital dermoscopy for surveillance of high-risk melanoma patients. A prospective longitudinal observational study.