Nucleotide excision repair (NER) removes helix-distorting DNA lesions through the ten subunit TFIIH complex, whose XPB and XPD translocase/helicase activities unwind DNA to enable damage verification and subsequent endonucleolytic DNA incisions. While most XPD mutations cause xeroderma pigmentosum, specific helicase-deficient mutations cause severe Cockayne syndrome (CS) features, including progressive neurodegeneration, for which the basis remains unclear. Here we show that loss of XPD helicase activity traps TFIIH in a futile repair cycle in which DNA is incised at the wrong position, leading to repeated DNA excision and resynthesis without removal of the lesion. Using C. elegans , we find that this futile DNA excision cycle produces severe neuronal dysfunction in vivo that depends on transcription-coupled NER activity and is rescued by preventing recruitment of helicase deficient TFIIH. These findings demonstrate that NER incisions can occur without XPD mediated damage verification and that persistent futile DNA excision cycles cause severe disease features, indicating that persistent NER intermediates are more pathogenic than unrepaired DNA lesions.

Data on the clinical characteristics of keratoacanthomas (KAs) associated with Muir-Torre syndrome (MTS) and xeroderma pigmentosum (XP) are limited. To compare the clinical features of KAs in patients with MTS and XP. Consecutive patients diagnosed with MTS or XP were evaluated for the occurrence of KA in a single dermatology centre. Age at onset, number, size, localization, association with cutaneous horn, and regression patterns of KAs were compared in both groups and with sporadic KAs. A total of 26 KAs were observed in 7 of 38 patients with XP and 11 lesions in 4 of 8 patients with MTS with a mean age at onset of 11.4±6.5 and 50.5±8.5 years, respectively. Most individuals with both syndromes presented with multiple KAs. In MTS patients, lesions involved both facial and truncal sites and were frequently >1 cm in diameter, and spontaneous regression commonly resulted in depressed or hypopigmented, atrophic scars surrounded by a thin rim, and mutilation was observed in one case. In contrast, KAs in XP patients were predominantly localized to the head and neck, with occasional mucosal involvement, and were sometimes associated with cutaneous horn and typically healed with minimal or no scarring. Sporadic KAs manifested mostly as solitary lesions, predominantly on the face, in 14 patients with a mean age of 60.2±14.2 years. KAs in XP and MTS patients differ with regards to age at onset, distribution, associated features, and regression patterns. Truncal involvement, larger size and prominent scarring favour MTS, whereas early onset, mucosal involvement, and association with cutaneous horn are more characteristic of XP.

Lung cancer is one of the most common and deadly forms of cancer worldwide, with >80% of cases being non‑small cell lung cancer. Its recurrence and drug resistance have been major challenges in clinical treatment, posing a serious threat to the lives of patients. The present study found that high xeroderma pigmentosum group C (XPC) expression markedly reduced the proliferation capacity and stem cell characteristics of the lung cancer cell lines A549‑XPC and H460‑XPC. In addition, XPC overexpression led to a decreased in the proportion of cells in the G2/M phase proportion, suggesting alterations in the cell cycle process. MTS assays showed that XPC overexpressing cells demonstrated markedly higher sensitivity to chemotherapy drugs compared with control cells. Furthermore, the clonogenic and anchorage‑independent spheroid formation capacities of the cells were markedly inhibited with high XPC expression and the phosphorylation levels of the JAK/STAT pathway and the expression levels of stemness‑associated markers were markedly altered. In vivo studies validated the effect of high XPC expression on tumorigenicity using a subcutaneous tumor model, with tumor volumes of 134.04±46.77 mm³ and 324.64±85.31 mm³ and weights of 164.24±76.16 mg and 434.70±115.72 mg for subcutaneously injected A549‑XPC and A549‑CTR cells, respectively. High expression of XPC in the A549 cells significantly affected tumor volume (P<0.05) and weight (P<0.01) in vivo. The present findings suggested that high XPC expression is associated with reduced proliferation, migration and stem cell‑like properties in lung cancer cells, enhances their sensitivity to chemotherapy drugs and suppresses tumor growth in vivo. These observations supported further investigation of XPC as a potential therapeutic target and prognostic marker for lung cancer, offering new strategies to improve treatment outcomes and prolong patient survival.

Repair of damaged DNA is a complex process, particularly when it is compacted into nucleosomes. There are a number of genetic disorders with deficiencies in DNA repair. Knowledge of the genes and proteins involved in these repair deficiencies is critical in developing an understanding of the molecular mechanisms utilized by proteins in the DNA repair pathways. One of these genetic disorders is xeroderma pigmentosum (XP), which is defective in nucleotide excision repair (NER). Patients in XP complementation group A (XP-A) are among the most severely affected with the lowest levels of DNA repair. The XPA protein, which is defective in these patients, plays a number of roles in the DNA repair process. One particularly important role proposed is acting as a processivity factor enabling endonucleases (XPF and XPG) and the XPB/TFIIH translocase to localize to damage sites using a processive mechanism of action. Another proposed role is in interacting with chromatin-remodeling proteins so as to enhance accessibility of lesions in nucleosomal DNA to endonucleolytic incision and other DNA repair activities. In XP-A cells, the XPA protein is proposed to be defective in ability to act as a processivity factor; endonucleases localize damage sites by a distributive mechanism and are also defective in incision of damaged nucleosomal DNA. This defect is corrected by recombinant normal human XPA. Mutations in exons 3 and 5 in the DNA binding domain of the XPA gene lead to loss of ability of XPA to act as a processivity factor. The mutation in exon 5 was found in two XP-A patients with severe XP. These studies emphasize the importance of correlating specific mutations in an XP gene and the resulting defect in a particular repair protein with the clinical severity of XP and could lead to development of novel therapeutic approaches for this disorder.

Japan's designated intractable disease (nanbyo) framework combines a population threshold with unresolved pathogenesis or treatment, long-term care needs, objective diagnostic criteria, and severity-linked assistance with medical expenses. We conducted a targeted narrative review of official Japanese sources and biomedical literature through August 3, 2026. Evidence ranged from regulatory approvals and randomized trials to observational, case-report, and preclinical data, so therapeutic maturity was assessed separately from mechanistic plausibility. We distinguished the 12 official skin/connective-tissue entries from six purposively selected designated entries or disease groups with decisive cutaneous phenotypes or Japan-specific translational value. The resulting 18-entry framework is illustrative, not exhaustive. It highlights Japan-specific biology or evidence regarding xeroderma pigmentosum, acquired idiopathic generalized anhidrosis, DPP-4 inhibitor-related bullous pemphigoid, generalized pustular psoriasis, cold-medicine-related SJS/TEN, anti-MDA5 dermatomyositis, and Nakajo-Nishimura syndrome. Recently approved indications or uses include dupilumab for adult bullous pemphigoid, IL-36 receptor blockade, topical COL7A1 gene delivery, autologous gene-corrected epidermal sheets, MEK inhibition, IL-1 blockade, and topical mTOR inhibition; JAK-interferon strategies remain investigational. We contend that Japan's designation infrastructure could become an interoperable translational platform linking natural-history cohorts, endotype-defined enrollment, mechanism-aligned endpoints, and multinational adaptive trials.

Two subpathways of nucleotide excision repair (NER), global genomic (GG-NER) and transcription-coupled NER (TC-NER), remove bulky DNA lesions such as cyclobutane pyrimidine dimers (CPDs). Xeroderma pigmentosum protein D (XPD) is a DNA helicase subunit within the transcription factor IIH complex that is important for DNA unwinding and damage verification during NER. Germline mutations in XPD can not only cause the cancer-prone disease xeroderma pigmentosum (XP), but also a combination of XP with Cockayne Syndrome (CS), a syndrome characterized by neurodegeneration and premature aging. While XP and XP/CS mutations in XPD disrupt NER, their specific effects on the NER subpathways are less well understood. In this study, we introduced two pairs of XP and XP/CS mutations into the yeast RAD3 gene, a homolog of human XPD. Our data indicates that yeast XP/CS mutants are more sensitive to UV radiation and have reduced NER capacity relative to the XP mutants. Using a damage mapping method named CPD sequencing (CPD-seq 2.0), we found that the XP/CS mutations abrogated repair by both GG-NER and TC-NER, while XP mutations impaired GG-NER but retained significant TC-NER activity. Consistent with these results, XPD mutant human cell lines established from individuals with XP/CS were sensitivity to Illudin S, an agent that induces damage repaired by TC-NER. Thus, we conclude that XP/CS mutations not only cause a more severe overall NER defect than XP mutations, but specifically disrupt the TC-NER subpathway, with this defect likely underlying the Cockayne Syndrome symptoms.