Natural small-molecules reverse Xeroderma Pigmentosum Complementation Group C (XPC) deficient-mediated drug-resistance in renal cell carcinoma.

BACKGROUND: Renal cancer is insensitive to radiotherapy or most chemotherapies. While the loss of the XPC gene was correlated with drug resistance in colon cancer, the expression of XPC and its role in the drug resistance of renal cancer have not yet been elucidated. With the fact that natural small-molecules have been adopted in combinational therapy with classical chemotherapeutic agents to increase the drug sensitivity and reduce adverse effects, the use of herbal compounds to tackle drug-resistance in renal cancer is advocated. PURPOSE: To correlate the role of XPC gene deficiency to drug-resistance in renal cancer, and to identify natural small-molecules that can reverse drug-resistance in renal cancer via up-regulation of XPC. METHODS: IHC was adopted to analyze the XPC expression in human tumor and adjacent tissues. Clinical data extracted from The Cancer Genome Atlas (TCGA) database were further analysed to determine the relationship between XPC gene expression and tumor staging of renal cancer. Two types of XPC-KD renal cancer cell models were established to investigate the drug-resistant phenotype and screen XPC gene enhancers from 134 natural small-molecules derived from herbal plants. Furthermore, the identified XPC enhancers were verified in single or in combination with FDA-approved chemotherapy drugs for reversing drug-resistance in renal cancer using MTT cytotoxicity assay. Drug resistance gene profiling, ROS detection assay, immunocytochemistry and cell live-dead imaging assay were adopted to characterize the XPC-related drug resistant mechanism. RESULTS: XPC gene expression was significantly reduced in renal cancer tissue compared with its adjacent tissue. Clinical analysis of TCGA database also identified the downregulated level of XPC gene in renal tumor tissue of stage IV patients with cancer metastasis, which was also correlated with their lower survival rate. 6 natural small-molecules derived from herbal plants including tectorigenin, pinostilbene, d-pinitol, polygalasaponin F, atractylenolide III and astragaloside II significantly enhanced XPC expression in two renal cancer cell types. Combinational treatment of the identified natural compound with the treatment of FDA-approved drug, further confirmed the up-regulation of XPC gene expression can sensitize the two types of XPC-KD drug-resistant renal cancer cells towards the FDA-approved drugs. Mechanistic study confirmed that GSTP1/ROS axis was activated in drug resistant XPC-KD renal cancer cells. CONCLUSION: XPC gene deficiency was identified in patient renal tumor samples, and knockdown of the XPC gene was correlated with a drug-resistant phenotype in renal cancer cells via activation of the GSTP1/ROS axis. The 6 identified natural small molecules were confirmed to have drug sensitizing effects via upregulation of the XPC gene. Therefore, the identified active natural small molecules may work as an adjuvant therapy for circumventing the drug-resistant phenotype in renal cancer via enhancement of XPC expression.

Xeroderma Pigmentosum: Novel Prophylactic and Therapeutic Approaches. Part One: Topical Zinc Sulfate 25% and Heat Dermabrasion plus Topical Trichloroacetic Acid.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease; relatively mild XP patients are sometimes designated as having pigmented xerodermoid or xerodermoid pigmentosum (XP-V), a variant of XP. It is commonly associated with many long-standing skin conditions and tumors, including malignancies, management of which is necessary to prevent the progress of the disease. The objective of the study was to report the use of a number of innovative therapeutic and prophylactic treatments, beyond surgery, such as topical 5-fluorouracil, topical imiquimod, other topical immunomodulators, or photodynamic therapy, in treating skin eruptions and their complications in XP patients. This was a prospective therapeutic interventional study in which 50 patients with XP-V were evaluated. Age of subjects ranged from 2 to 50 years with a mean age of 18 years. This study was divided into two parts. In part one, patients were treated by applying topical zinc sulfate 25% twice daily on entire face for 2 months, then once daily for several months or years. In another instance, two women were treated with heat dermabrasion with needle diathermy on the entire face under local anesthesia, followed by application of trichloroacetic acid 35% peeling in a single session. In part two, topical podophyllin 25% was used as therapy for 18 patients, all of whom had XP complications, such as keratoacanthoma, basal cell carcinomas and squamous cell cancers.1 Podophyllin was applied to the lesions until complete resolution was documented. All patients treated with topical zinc sulfate 25% responded well as determined by clearance of actinic keratoses (ActK) and small malignant lesions, minimization of pigmented freckles, prevention of new lesions, and ceased progress of eruptions. Heat dermabrasion administered in a single session resulted in the clearance of pigmented freckles, ActK, and small tumors, and cessation of new eruptions during follow-up that continued for up to 6 years.

Xeroderma Pigmentosum: Part Two: Treatment of Skin Tumors with Topical Podophyllin 25% in Benzoin.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease; relatively mild XP patients are sometimes designated as having pigmented xerodermoid or xerodermoid pigmentosum (XP-V), a variant of XP. It is commonly associated with many long-standing skin conditions and tumors, including malignancies, management of which is necessary to prevent the progress of the disease. The objective of the study was to evaluate an innovative therapeutic treatment, beyond surgery, surgical excision, cryotherapy, electrocautery and curettage, or Mohs surgery, for the management of skin tumors in XP.This was a prospective therapeutic interventional study comprising 50 patients with XP-V. Age of subjects ranged from 2 to 50 years, with a mean age of 18 years. Several measures were evaluated in part one of this study, and a number of others (as reviewed in part one) were successful in prophylaxis of skin tumors in XP as well as in treating earlier stigmata of XP; however, these measures were notably less successful in treating well-developed skin tumors in XP patients, and 18 of the 50 patients evaluated in part one had well-developed tumors (total 22 lesions) refractory to treatments. Podophyllin 25% in 100-mL tincture of benzoin was applied topically to lesions until complete resolution was documented in 18 patients with XP complications, such as keratoacanthoma (KA), basal cell carcinoma, or squamous cell carcinoma. Topical podophyllin 25% in benzoin was a less destructive alternative treatment for skin cancer and KA in XP patients.

Evaluation of the effectiveness and safety of combined oral and topical photoprotection with a standardized extract of Polypodium leucotomos (Fernblock®) in a Moroccan population with xeroderma pigmentosum.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal-recessive genodermatosis resulting from a DNA-repair defect syndrome. The purpose was to evaluate the prevention on new malignant lesions in patients taking a supplement with Fernblock® (Polypodium leucotomos extract [PLE]) and secondarily correlation with the photoprotective behavior. METHODS: A prospective, single-center and open cohort study was conducted over a 12-month period. The study was performed in Morocco. Optimal photoprotection behavior was recommended. Patients were instructed to take one capsule containing 480 mg of Fernblock® and 5 mcg vitamin D and to apply sunscreen with a SPF50+ and Fernblock® every 2 h during sun exposure. The demographic, clinical, and dermatoscopic patient data were collected at baseline (T0) and following visits at 3 months (T3), 6 months (T6), and 12 months (T12) when it was assessed: Investigator Global Assessment (IGA), Patient/Guardian Global Assessment (PGA), Patient/Guardian Satisfaction Questionnaire, and Photographic and Adverse Events Registration. Pertinent statistical study was performed. RESULTS: Eighteen patients completed the study. Eleven patients (61%) finished the study without new lesions. Seven patients developed new lesions by the end of the study. Among them, only 30% showed an ideal photoprotective behavior. The lack of an optimal photoprotective behavior increased the probability of developing lesions by 2.5 times with 95% confidence interval. CONCLUSIONS: In our study, more than 60% of patients taking a supplement with Fernblock® did not develop new lesions, and furthermore, we detected that patients following almost ideal photoprotection were 2.5 times less likely to develop NMSC lesions.

Actual state of knowledge in the field of diseases related with defective nucleotide excision repair.

Xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) are rare genetic diseases characterized by a large range of clinical symptoms. However, they are all associated with defects in nucleotide excision repair (NER), the system responsible for removing bulky DNA lesions such as those generated by UV light: cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone photoproducts (6-4 PPs). Over the past years, detailed structural and biochemical information on NER-associated proteins has emerged. In the first part of the article we briefly present the main steps of the NER pathway with an emphasis on the precise role of certain proteins. Further, we focus on clinical manifestations of the disorders and describe the diagnostic procedures. Then we consider how current therapy and advanced technology could improve patients' quality of life. Although to date the discussed diseases remain incurable, effective sun protection, a well thought out diet, and holistic medical care provide longer life and better health. This review summarizes the current state of knowledge regarding the epidemiology of NER-associated diseases, their genetic background, clinical features, and treatment options.

High prevalence of vitamin D deficiency in patients with xeroderma pigmetosum-A under strict sun protection.

BACKGROUND/OBJECTIVES: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by defective repair of ultraviolet (UV) irradiation-induced DNA damage and high risk of skin cancer. Thus, these patients require strict photoprotection. Considering the importance of UV-mediated cutaneous vitamin D production, such rigorous photoprotection would cause vitamin D deficiency. Then, we have studied the vitamin D status in patients with XP-A, a group requiring the most strict photoprotection. SUBJECTS/METHODS: Twenty-one patients with XP-A (aged 6-25) were evaluated for their vitamin D intake, serum levels of 25-hydroxy-vitamin D (25OHD) and parathyroid hormone (PTH). Vitamin D intake was assessed by a 2-day food weighing method. RESULTS: Median dietary intake of vitamin D was 4.1 µg/day, and the median concentrations of serum 25OHD and PTH were 7.7 and 49.9 pg/ml, respectively. In 76% of the patients, serum 25OHD level was lower than 10 ng/ml, indicating vitamin D deficiency. Vitamin D intake and serum 25OHD level were significantly lower in patients under enteral nutrition (EN) than those with oral intake (OI). Multivariate analyses revealed that EN was a significant predictor of decreased serum 25OHD level (ß coefficient=-0.59, P=0.03). CONCLUSIONS: Vitamin D deficiency is highly prevalent in XP-A patients, and supplementation should be considered to avoid unfavorable skeletal consequences in these patients. In addition, determination of dietary vitamin D requirement has been a difficult work issue in the decision of dietary reference intakes (DRIs) because of its cutaneous production. Data from XP patients would yield useful information for the determination of DRIs for vitamin D.

Auditory analysis of xeroderma pigmentosum 1971-2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration.

To assess the role of DNA repair in maintenance of hearing function and neurological integrity, we examined hearing status, neurological function, DNA repair complementation group and history of acute burning on minimal sun exposure in all patients with xeroderma pigmentosum, who had at least one complete audiogram, examined at the National Institutes of Health from 1971 to 2012. Seventy-nine patients, aged 1-61 years, were diagnosed with xeroderma pigmentosum (n = 77) or xeroderma pigmentosum/Cockayne syndrome (n = 2). A total of 178 audiograms were included. Clinically significant hearing loss (>20 dB) was present in 23 (29%) of 79 patients. Of the 17 patients with xeroderma pigmentosum-type neurological degeneration, 13 (76%) developed hearing loss, and all 17 were in complementation groups xeroderma pigmentosum type A or type D and reported acute burning on minimal sun exposure. Acute burning on minimal sun exposure without xeroderma pigmentosum-type neurological degeneration was present in 18% of the patients (10/55). Temporal bone histology in a patient with severe xeroderma pigmentosum-type neurological degeneration revealed marked atrophy of the cochlear sensory epithelium and neurons. The 19-year mean age of detection of clinically significant hearing loss in the patients with xeroderma pigmentosum with xeroderma pigmentosum-type neurological degeneration was 54 years younger than that predicted by international norms. The four frequency (0.5/1/2/4 kHz) pure-tone average correlated with degree of neurodegeneration (P < 0.001). In patients with xeroderma pigmentosum, aged 4-30 years, a four-frequency pure-tone average ≥10 dB hearing loss was associated with a 39-fold increased risk (P = 0.002) of having xeroderma pigmentosum-type neurological degeneration. Severity of hearing loss parallels neurological decline in patients with xeroderma pigmentosum-type neurological degeneration. Audiometric findings, complementation group, acute burning on minimal sun exposure and age were important predictors of xeroderma pigmentosum-type neurological degeneration. These results provide evidence that DNA repair is critical in maintaining neurological integrity of the auditory system.

The cerebro-morphological fingerprint of a progeroid syndrome: white matter changes correlate with neurological symptoms in xeroderma pigmentosum.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive progeroid syndrome. It has recently been shown that the underlying DNA repair defect plays a central role in the aging process. In addition to skin symptoms, various premature neurological abnormalities have been reported. METHODOLOGY/PRINCIPAL FINDINGS: We present the clinical neurological phenotype in 14 XP patients (seven subtypes), in seven of these patients together with conventional and multiparametric advanced MRI data to assess the macrostructural and microstructural cerebral morphology in comparison to controls, including volumetric measurements, MR spectroscopy ((1)H MRS), and diffusion tensor imaging (DTI). Clinical hallmarks were spinocerebellar ataxia, pyramidal tract signs, and mild cognitive deficits. DTI demonstrated significantly reduced WM directionality in all regions investigated, i.e. the thalamus, the corticospinal tracts and the dorsal corpus callosum. Single patients showed a marked relative hippocampal volume reduction, but the patients were not different from controls in the volumetric measurements of hippocampal and whole brain volumes at group level. However, (1)H MRS demonstrated that the hippocampal formation was metabolically altered. CONCLUSIONS: The most prominent feature was the white matter affectation, as assessed by DTI, with volume and directionality reductions of the fiber projections involving both the craniocaudal fibers and the interhemispheric connections. These findings, although heterogeneous among the study sample, could be correlated with the clinico-neurological symptoms. The imaging findings support the position that myelin structures degrade prematurely in the brain of XP patients.

Xeroderma pigmentosum family support group: Helping families and promoting clinical initiatives.

The past two decades of research into Xeroderma pigmentosum (XP), an autosomal recessive disease, has been marked by significant progress in understanding the molecular basis of this rare disease. More importantly, especially from the perspective of the affected families, is that this knowledge has been applied to diagnose the condition both in utero as well as in the very early days of life. The eight known XP genes and their different phenotypes present a number of challenges that the XP Workshop sponsored by the NIH in 2010 has highlighted. There is little current treatment specifically designed for any of the XP types other than standard dermatological and neurological evaluations and care. The Xeroderma Pigmentosum Family Support Group (XPFSG) is dedicated to serving families with children and adults with all forms of XP and to help them better understand the condition, to identify practical measures which can be taken by the XP patients and their families to mitigate the effects of the disease, and to serve as patient advocates to help families discuss issues with their physicians. We summarize our efforts in terms of outreach within the US and abroad to affected families and discuss XPFSG-sponsored clinical initiatives that include molecular diagnoses, treatment, and initial proof-of-concept studies that can, if successful, improve the lives of XP patients in the near term.

Running posture and step length changes immediately after chiropractic treatment in a patient with xeroderma pigmentosum.

OBJECTIVE: This case study reports on selected measures of locomotion (running) in a 5-year-old patient with xeroderma pigmentosum after chiropractic care. CLINICAL FEATURE: A 5-year-old female patient (16.4 kg, 99.1 cm) with xeroderma pigmentosum (type A) volunteered to participate in the experiment with the consent of her parents. The patient had well-documented signs of delayed fine motor (eg, difficulty with writing, coloring, cutting) and gross motor control (eg, balance and coordination dysfunction and falling while running), and delayed speech. INTERVENTION AND OUTCOMES: Trunk forward lean angles, step lengths, and hip horizontal translations were assessed by video as the participant ran as fast as possible down a laboratory runway. After chiropractic manipulation (adjustments), the patient reduced the trunk forward lean angle to become more vertical (P = .000). In addition, the patient experienced an increase in step length (P = .031). No significant change in lateral translation was observed after the intervention. CONCLUSION: For this patient with xeroderma pigmentosum, chiropractic manipulation (adjustments) resulted in immediate changes in running performance. Further investigation is needed to examine the effect of chiropractic on locomotion in both symptomatic and asymptomatic patients.

T4 endonuclease V: review and application to dermatology.

BACKGROUND: T4 endonuclease V was originally isolated from Escherichia coli infected with T4 bacteriophage. It has been shown to repair ultraviolet (UV)-induced cyclobutane pyrimidine dimers in DNA, which, when unrepaired, contribute to mutations that result in actinic keratoses and non-melanoma skin cancers (NMSC). This is a particular concern in patients with genetic defects in their DNA repair systems, especially those with xeroderma pigmentosum (XP). When packaged in liposomes and applied topically, T4 endonuclease V can traverse the stratum corneum and become incorporated within the cytoplasm and nucleus of epidermal keratinocytes and Langerhans cells. OBJECTIVE: To review all major studies evaluating the efficacy of T4 endonuclease V in animals and humans, the toxicity and safety profile of the topical medication and its potential clinical uses. METHODS: A literature search was performed through PubMed/Medline, using the keywords 'T4N5', 'T4 endonuclease V' and 'dimericine'. Papers found in the bibliographies of those identified in the initial search and deemed relevant were also included. CONCLUSION: This enzyme increases the repair of UV-damaged DNA and produces other beneficial effects on UV-damaged cells. In clinical trials in XP patients, topical application of liposome-encapsulated T4 endonuclease V reduced the incidence of basal cell carcinomas by 30% and of actinic keratoses by > 68%. Adverse effects were minimal, and there was no evidence of allergic or irritant contact dermatitis. Although the photoprotective effect of T4N5 has been investigated only in XP patients, the possibility exists that it may benefit others likely to develop premalignant keratoses and NMSC, such as organ transplant recipients receiving immunosuppressive therapy and individuals who have had numerous psoralen plus UVA photochemotherapy treatments. It may be also be effective for normal individuals.

The evaluation of thermal cisplatin sensitization in normal and XP human cells using mild hyperthermia at 40 and 41 degrees C.

The effect of protracted mild hyperthermia treatment at 40 and 41 degrees C given, concurrently with cisplatin, was evaluated in human normal AG1522 and human mutant XPA cells. While mild hyperthermia itself for up to 6 hours showed little to no toxic effects, it did result in significant sensitization of response to cisplatin treatment. Sensitization for the normal and mutant cell line was comparable, indicating that nucleotide excision repair (NER) probably does not have a role in this process. For the 41 degrees C heating, thermotolerance developed and heating times greater than 4 hours resulted in protective effects from cisplatin cytotoxicity. This was not observed for heating at 40 degrees C for up to 6 hours.

Rickets in xeroderma pigmentosum.

Xeroderma pigmentosum patients are advised to strictly avoid sun exposure to prevent ultraviolet-induced DNA damage. We describe a 2 1/2 years old boy having xeroderma pigmentosum, who also developed rickets. He was given one injection of vitamin D along with dietary vitamin D supplements to which he responded. He is being followed- up regularly in outdoor clinic with the advice to the parents to continue dietary vitamin D supplements and to avoid sun exposure.

Brainstem and basal ganglia lesions in xeroderma pigmentosum group A.

Xeroderma pigmentosum group A (XPA) is a hereditary disorder characterized by cutaneous symptoms and progressive neurodegeneration. Since XPA patients exhibit peripheral neuropathy, neuronal deafness, rigidity, dysphagia, and laryngeal dystonia, it is indispensable for investigation of the neurodegeneration to analyze brainstem and basal ganglia lesions clinically and pathologically; we have previously shown the role of oxidative stress in the development of basal ganglia lesions. Here we immunohistochemically examined the expression of neurotransmitters, calcium-binding proteins, and neuropeptides in the brainstem, basal ganglia, and thalamus in 5 XPA autopsy cases. In the brainstem, immunoreactivity for tyrosine hydroxylase, tryptophan hydroxylase, and calbindin-D28K was severely reduced throughout the brainstem in all the XPA cases. Nevertheless, the expressions of parvalbumin, substance P, and methionine-enkephalin in the brainstem were comparatively preserved; the exception being reduced immunoreactivity for them in the cochlear and dorsal column nuclei in 3 cases. The large cell neurons in the putamen were preferentially reduced, the immunoreactivity for tyrosine hydroxylase reflecting the dopaminergic afferent and efferent pathways was severely affected, and the expression of 3 calcium binding proteins (i.e. parvalbumin, calbindin-D28K, and calretinin) was disturbed in various ways. The expression of substance P and methionine-enkephalin, which are involved in the efferent pathways in the basal ganglia, in the globus pallidus and substantia nigra was spared. It is speculated that the selective damage to the dopamine system in the basal ganglia and the disturbed monoaminergic expression in the brainstem could be related to clinical abnormalities such as the rigidity, laryngeal dystonia, and several neurophysiological changes. Functional analysis of autopsy brains will facilitate clarification of the pathogenesis of the neurodegeneration in XPA.

Peeling químico con ácido tricloroacético. Un peeling clásico de máxima actualidad / Chemical peeling with trichloroacetic acid. A classical peeling of maximum present time

El peeling o exfoliación química consiste en la destrucción de la epidermis y dermis papilar mediante la aplicación de una sustancia química corrosiva con la finalidad de conseguir una nueva epidermis y dermis superficial de mejores cualidades cosméticas. Entre ellos, el peeling de mediana potencia más utilizado en la práctica es el de ácido tricloracético en concentraciones del 11-35%, y a pesar de tener más de 50 años de historia sigue considerándose hoy como un estándar en este procedimiento. Se puede aplicar tanto en pincelación como en mascarilla y consigue resultados muy satisfactorios en cicatrices moderadas de acné, queratosis solares, manchas y léntigos faciales. Su principal inconveniente en personas de fototipo mediterráneo es la hiperpigmentación residual, que puede evitarse mediante la fotoprotección estricta (AU)

Photoactivation of DNA thiobases as a potential novel therapeutic option.

The thiopurines, 6-thioguanine and 6-mercaptopurine, are antileukemic agents that are incorporated into DNA following retrieval by the purine salvage pathway (see [1] for a review). Their toxicity requires active DNA mismatch repair (MMR), and thiopurine resistance is an acknowledged phenotype of MMR-defective cells [2, 3]. In addition to these direct cytotoxic effects, DNA thiobases have distinctive photochemical properties [4], the therapeutic potential of which has not been extensively evaluated. We report here that the thiopyrimidine nucleoside 4-thiothymidine is incorporated into DNA. It does not induce MMR-related toxicity, but it interacts synergistically with UVA light and dramatically sensitizes cultured human cells to very low, nonlethal UVA doses. 4-thiothymidine induced UVA dose enhancements of around 100-fold in DNA repair-proficient cells. Nucleotide excision repair-defective xeroderma pigmentosum cells were sensitized up to 1000-fold, implicating bulky DNA photoproducts in the lethal effect. The synergistic action of thiothymidine plus UVA required thymidine kinase, indicating a selective toxicity toward rapidly proliferating cells. Cooperative UVA cytotoxicity is a general property of DNA thiobases, and 6-thioguanine and 4-thiodeoxyuridine were also UVA sensitizers. Thiobase/UVA treatment may offer a novel therapeutic approach for the clinical management of nonmalignant conditions like psoriasis or for superficial tumors that are accessible to phototherapy.

Cadmium mutagenicity and human nucleotide excision repair protein XPA: CD, EXAFS and (1)H/(15)N-NMR spectroscopic studies on the zinc(II)- and cadmium(II)-associated minimal DNA-binding domain (M98-F219).

Human XPA is a 31 kDa protein involved in nucleotide excision repair (NER), a ubiquitous, multi-enzyme pathway responsible for processing multiple types of DNA damage in the eukaryotic genome. A zinc-associated, C4-type motif (C105-X(2)-C108-X(17)-C126-X(2)-C129) located in the minimal DNA-binding region (M98-F219) of XPA (XPA-MBD) is essential for damaged DNA recognition. Cadmium is a known carcinogen and can displace the zinc in many metal-binding proteins. It has been suggested that the carcinogenic properties of cadmium may result from structural changes effected in XPA when Cd(2+) is substituted for Zn(2+) in the metal-binding site. The solution structure of XPA-MBD containing zinc(II) has recently been determined [Buchko et al., (1998) Nucleic Acids Res., 26, 2779-2788; Buchko et al., (1999) Biochemistry, 38, 15116-15128]. To assess the effects of cadmium(II) substitution on the structure of XPA-MBD, XPA-MBD was expressed in minimal medium supplemented with cadmium acetate to yield a protein that was almost exclusively (>95%) associated with cadmium(II) (CdXPA-MBD). Extended X-ray absorption fine structure spectra collected on ZnXPA-MBD and CdXPA-MBD in frozen (77 K) 15% aqueous glycerol solution show that the metal is coordinated to the sulfur atoms of four cysteine residues with an average metal-sulfur bond length of 2.34 +/- 0.01 and 2.54 +/- 0.01 A, respectively. Comparison of the circular dichroism, two-dimensional (1)H,(15)N-HSQC, and three-dimensional (15)N-edited HSQC-NOESY spectra of ZnXPA-MBD and CdXPA-MBD show that there are no structural differences between the two proteins. The absence of major structural changes upon substituting cadmium(II) for zinc(II) in XPA suggests that cadmium-induced mutagenesis is probably not due to structural perturbations to the zinc-binding core of XPA.