Xeroderma Pigmentosum Is Associated With Malfunction In What Types Of Dna Repair?

Curr Med Lit Dermatol. Writer manuscript; available in PMC 2022 October 21.

Published in final edited class every bit:

Curr Med Lit Dermatol. 2008; xiii(ii): 41–48.

PMCID: PMC3198809

NIHMSID: NIHMS111831

Diagnosis of Xeroderma Pigmentosum and Related Dna Repair-Scarce Cutaneous Diseases

James E Cleaver

University of California, San Francisco (UCSF) Cancer Center, University of California, San Francisco, CA, USA

Xeroderma pigmentosum and related repair-deficient diseases

Xeroderma pigmentosum (XP) is a rare, human, autosomally inherited skin and neurodegenerative disease [one] that is associated with a very high incidence of peel and mucous membrane cancers due to exposure to normal sunlight. These cancers include squamous and basal prison cell carcinomas and melanomas, and are predominantly acquired past exposure to ultraviolet B (UVB) radiation, although UVA cannot be excluded [2,3]. UVB (280–320 nm) is the shorter wavelength radiation in sunlight that is responsible for most sun-induced cancers in the general population, as well as in XP patients. The relative incidence of the various forms of skin cancers in XP patients is similar to that in the general population [4].

XP was the first nucleotide excision repair (NER)-related disease to be identified [ane]. Currently, the consummate family of NER-related diseases includes XP, XP with neurological complications, the XP variant (XPV), Cockayne syndrome (CS), cerebro-oculo-facio-skeletal syndrome (COFS), a mild UV-sensitive syndrome (UV^S), trichothiodystrophy (TTD), and the combinations XP/CS and XP/TTD [5–8]. These diseases show overlapping symptoms associated with cancer, developmental delay, immunological defects, neuro-degeneration, retinal degeneration, and premature aging.

The NER-related diseases are associated predominantly with failures in Deoxyribonucleic acid repair or replication in cells that incorporate UV-induced photoproducts in their Dna. These photoproducts include the (5–5) and (6–6) cyclobutane pyrimidine dimers (CPDs) and the (six–4) pyrimidine pyrimidinone dimers (PDs) that can involve T and C pyrimidines [ix]. When these photoproducts are unrepaired due to NER deficits, cytosine deamination and replication errors lead to characteristic C→T mutations (especially CC→TT mutations), which are institute at high frequencies in p53 and other genes in solar-induced pare cancers of XP patients and others [10–16].

The diagnostic problem

Approximately one person per one thousand thousand suffers from XP, except for in a few locations that prove founder effects [17–20]. The rarity of the disease means that diagnosis is not frequently required; hence, robust diagnostic methods have non been adult. Many who have engaged in basic inquiry into the genetic and molecular basis of XP accept provided informal services for patient and prenatal diagnosis using specialized DNA repair techniques [21–23]. Diagnosis has rarely been rapid, and many cases have required extensive research when the patient proved to have novel or rare mutations [17,24,25].

Several procedural as well as technical bug accept precluded the evolution of routine diagnostic services for XP patients, including the size of the potential market, the technologies required, and licensing problems. The potential marketplace size is small, which inhibits costly investment in novel technological approaches such as sequencing arrays. When the current author'south laboratory was carrying out diagnostic services, there would be a asking for approximately i new diagnosis per month, each of which took approximately 6 weeks to complete [22,26]; this number is too few to support a commercial, fee-for-service diagnosis. Sequencing the candidate gene would be the ultimate standard for positive identification of an XP patient, simply this approach tin but be applied effectively once the gene in question is identified. More than 90% of all XP cases are deemed for by mutations in one of four genes: XPA, XPC, XPD, and XPV [27]. The need to diagnose a illness that has numerous underlying genes presents a technical challenge, especially since the data base is small, the number of mutations that occur in these genes has not been saturated, and new alleles keep to be identified.

A further complexity, unique to the American market, is that the Clinical Laboratory Improvement and Accountability Human action of 1988 regulates the laboratories that can perform patient-specific diagnostic tests. This has precluded the power of enquiry laboratories from using their specialized techniques for patient diagnosis and obtaining reimbursement. One approach that has been successful is for a dedicated diagnostic laboratory to provide generic DNA sequencing services for a large number of rare diseases, thus increasing their potential marketplace. However, XP has too many potential alleles to exist diagnosed price-effectively in this fashion. Therefore, at nowadays, almost methods for diagnosis depend on functional assays of UV sensitivity and DNA repair to delimit the sequencing required.

A rapid and robust routine diagnostic method is needed for confirmation of a clinical diagnosis of XP; and one that besides provides essential information that could exist employed in the dermatological clinic or commercial sector without the demand for specialized technical approaches. In subsequent sections of this article, there will exist a brief review of current noesis of the biochemistry and genetics of XP, as well as a discussion of diagnostic techniques. An approach that the electric current author'due south laboratory is developing and validating volition also exist presented.

Biochemistry

The NER system recognizes and repairs Dna damage that consists of UV-induced photoproducts and large Deoxyribonucleic acid adducts [nine]. Although the CPDs and (half-dozen–four)PDs are the major damage of concern in XP pathology, chemical adducts that are also substrates for NER include those produced by carcinogens or chemotherapy agents, such as N-acetoxy-N-acetyl aminofluorene (AAAF), benzo(a)-pyrene, aflatoxin, photoactivated psoralens, and cis-platinum. The neurological degeneration seen in some patients may be due to similar kinds of unrepaired damage generated endogenously by reactive oxygen species leaking from mitochondria or other sources [28,29].

The NER organisation consists of a serial of reactions by which DNA damage is recognized in nuclear Dna inside unlike functional domains (Figure ane) [30,31]. Damage in transcriptionally inactive regions is detected by the damage Dna-binding protein complex DDB1/DDB2 (DDB2 is also known as XPE) and by XPC/homologous recombination protein 23B (HR23B)/centrin2. Damage in transcriptionally active regions is detected through arrest of the transcriptional mechanism involving RNA polymerases I and Ii, and requires the CSA and CSB proteins that are mutated in the CS disorder. The damaged site is and so remodeled through a series of preincision complexes [31–33]. XPA, replication protein A (RPA), XPC, and the transcription DNA repair factor IIH (TFIIH) assemble in a random but cooperative society on the damaged site. They form an unstable preincision complex that is stabilized once the Deoxyribonucleic acid is unwound by the ATPase activeness of XPB and the ATPase/helicase activity of XPD in TFIIH [31–33]. TFIIH is a 10-component transcription factor containing XPB and XPD. XPC recruits XPG and is displaced from the circuitous. Cleavage and so occurs on both sides of the damaged site, firstly by the XPG three′ nuclease and then past the XPF/excision repair cantankerous-complementing protein 1 (ERCC1) 5′ nuclease. The nucleases are anchored by the XPA/RPA complex, which serves to define the cleavage sites and strand specificity. Once the damaged oligonucleotide is removed, a patch is resynthesized by the proliferating prison cell nuclear antigen, the polymerases delta, epsilon, or kappa (δ, εor κ), and a ligase enzyme [xxx,34]. In quiescent cells, ligation involves X-ray repair cross-complementing protein 1 (XRCC1) and ligase III; in proliferating cells, ligation involves ligase I [35].

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Pathways of nucleotide excision repair and diagnostic methods. The proteins indicated are the primary ones involved in XP; bounden partners and other components are omitted for clarity. Left cavalcade: schematic of NER. The initial damage (elevation) is recognized by the XPE and XPC DNA-binding proteins. The damaged site is then remodeled through a series of preincision complexes, indicated inside the hatched box [31–33]. XPA, RPA, and XPC/TFIIH grade an initial preincision circuitous that is stabilized once the DNA is unwound by the ATPase activity of XPB and ATPase/helicase activity of XPD in TFIIH [31–33]. XPC recruits XPG and is displaced from the complex. Cleavage then occurs on both sides of the damaged site, firstly by the XPG 3′ nuclease and then by the XPF/ERCC1 five′ nuclease. One time the damaged oligonucleotide is removed, a patch is resynthesized and is completed by polymerases and ligases. Right column: steps in NER that have been addressed for diagnosing repair by (top to bottom) damage detection, protein expression by immunohistochemistry, strand breakage, damage removal, and unscheduled Dna synthesis.

BrdUrd: bromodeoxyuridine; dThd: tritiated thymidine; ERCC1: excision repair cross-complementing protein i; HRP: horseradish peroxidase counter stain for XPC antibody; NER: nucleotide excision repair; RPA: replication poly peptide A; TFIIH: transcription/DNA repair cistron IIH; UV: ultraviolet; XP: xeroderma pigmentosum.

NER can remove DNA harm earlier Dna replication begins and, consequently, plays a major role in reducing the amount of harm that becomes fixed as mutations during replication [36]. Specialized polymerases are required to replicate DNA photoproducts because the normal Dna polymerases – alpha, delta, and epsilon (α, δ, and ε) – cannot arrange large distortions such as Deoxyribonucleic acid photoproducts or adducts in their active sites [x,37]. These harm-specific polymerases take relaxed substrate specificity, and the most of import is the low-fidelity polymerase Pol eta (η) [38]. This is mutated in the XPV condition, which is often clinically duplicate from NER-deficient XP [39].

Genetics of XP

The full number of genes direct involved in NER is estimated to exist approximately 40 [forty]. Merely eight are known to be associated with XP, two with CS, and four with TTD. Many of the other genes are apparently essential and would be lethal if mutated. For example, consummate loss of role in both alleles is not seen in XPB or XPD patients because the proteins are essential components of TFIIH, which has 10 component proteins [41–44]. Mutations in ERCC1 take been reported in merely i patient (with COFS), which was neonatally lethal [24]. Some patients may take such mild clinical disease that they blend into the population of other sun-sensitive individuals, and a number of these patients accept been defined equally having UV^S, which tin overlap with CS [45–47]. Novel genes could yet be found to cause these diseases. There may as well be new variant diseases that could be candidates for genetic analysis.

Diagnostic approaches

A directly sequencing approach is challenging for XP as it requires the sequencing of upwardly to a full of 25 kb of coding sequence scattered over >100 exons of eight genes; this requires multiplex polymerase chain reaction amplification and independent cloning and sequencing in most cases. However, CS unremarkably involves only one of two genes, CSA or CSB; directly sequencing of these genes for a new patient would be feasible. CS, particularly when associated with XP-like symptoms, can besides be caused past mutations in XPB, XPG, and particularly XPD; therefore, there remains a part for functional cellular assays in some cases of this disease [48]. Advances in multiplex amplification of large numbers of exons simultaneously, together with the falling costs of high-book Dna sequencing, should eventually atomic number 82 to a cost-effective approach of screening for mutations, fifty-fifty in rare diseases [49].

Many of the stages of NER can exist exploited in order to assay for the presence of mutations that would be diagnostic for XP (Effigy one); however, not all of these methods tin exist conveniently transferred into the diagnostic context. The bulk require access to a specialty laboratory with a calibrated UV source, and methods for analyzing DNA metabolism and photoproducts likewise equally transfer of complementing genes.

Specialized laboratory tests that the current author and others have used at various times include (Effigy 1): UV sensitivity and plasmid transfection with or without cotransfection of wild-type genes to complement the defect [21,25], photoproduct formation and excision [l], unmarried-strand intermission production during excision [22,51,52], and assay of incorporation of new bases during the repair synthesis phase (unscheduled Dna synthesis) [53,54]. These tests have all been used in various contexts for diagnosis of patients and for prenatal diagnosis [22,23,25,26,55]. To identify the gene that is mutated, the methods require a panel of characterized XP cells with which to compare a candidate jail cell line by jail cell-fusion techniques [53], or cDNA expression systems with the panel of XP genes for co-transfection [25].

These approaches all necessitate cells from a patient to be established in culture and their sensitivity to UV lite adamant, relative to that of cells from normal individuals. Fibroblasts from the skin or lymphoid cells from the blood have proven to be every bit usable [17]. Detection of increased sensitivity to UV light will only identify a patient as belonging to one of the XP groups (A through to M). Group Eastward represents mild disease with small repair deficit; its classification has proved hard and misidentification has occurred in the past [56,57].

Cells from patients with XPV are only slightly sensitive to UV and their identification requires an additional sensitization pace by growth in caffeine (a kinase inhibitor with a broad range of activity) subsequently UV irradiation [58,59]. This sensitization is due, in part, to inhibition of an clutter telangiectasia and Rad3-related protein (ATR)-dependent phosphorylation pathway in Pol η-deficient cells, just the consummate explanation remains unclear. The sensitization is sufficient to place a patient with XPV, after which sequencing of the Pol η cistron would confirm the diagnosis [39]. If cells are not sensitive to UV light, with or without caffeine, this would be sufficient to exclude a diagnosis of XP and no further test would be required.

Immunohistochemistry as a route to identification of mutated XP genes

Many inquiry groups have used the methods described higher up for identifying new XP patients (Figure 1); nonetheless, these are complex, specialized technical approaches that are non routinely available in dermatopathology laboratories. The current author's laboratory has explored the potential of using a technique that is more readily available – that of immunohistochemistry (de Feraudy and Cleaver, unpublished observations). Virtually XP patients come to the attention of clinicians because of photosensitivity and incipient sun harm in the form of excessive freckling, keratoses, or early skin cancers. The bulk of dermatological examinations of potential XP patients include biopsy of suspicious lesions that are then fixed and embedded in alkane series blocks for histological examination. These blocks are archived and can be accessed for subsequent analysis of XP protein expression without subjecting the patient to farther invasive procedures.

Mutations in XP genes encompass the complete spectrum of loss-of-office changes, including stop codons, frame shifts, and splice-site and missense mutations. The majority of these result in reduced or absent protein levels [17,25,27,39,44,60]. Mutations in XPB and XPD, of which at least ane allele is missense, but have small-scale effects on the protein levels [44,61,62], unlike mutations in the p8 component of TFIIH that destabilize protein levels [63,64]. Therefore, it is likely that most mutations in XPA, XPC, XPG, XPF, and XPV, but less so for XPB and XPD, will cause a reduced amount of protein detectable past immunohistochemistry of fixed tissue with the advisable antibody or panel of antibodies. Many of these antibodies are now bachelor from commercial sources. Preliminary studies carried out in the present writer's laboratory have demonstrated that XPC is highly expressed in the basal layer of the peel, with decreasing levels as cells drift through the epidermis. This laboratory is assessing the suitability of this method as a routine dermatopathology process, since immunohistochemistry is an accepted method covered by most The states medical insurance plans. However, an evaluation of the sensitivity and precision of a range of commercial antibodies for detecting XP mutations, and the accurateness of predictions, is still needed. While the method should prove useful for identifying XPA, XPC, and XPV patients, its utility for XPB and XPD patients may be much less as these patients do non take a meaning reduction in poly peptide levels [61]. In addition, mild cases acquired by leaky mutations with significant levels of protein expression may also exist hard to identify unequivocally. Standards consisting of paraffin blocks of peel biopsies from known patients, or pellets of tissue civilization cells from XP patients would assistance in validation of the method. A further development of this approach could be antibody arrays comprising a panel of XP antibodies on which extracts of peripheral lymphocytes could bind.

Diagnosis and prognosis

Any new patient requires an initial confirmation, past assessment of UV sensitivity, that they genuinely do have XP; the gene involved must then be identified. The next question is what use is to be made of the information since in that location are no cures, only palliative procedures, to offer the prospective patient? At its simplest, a diagnosis of XP dictates a lifetime of stringent protection from sun exposure for patients and their families. Nonetheless, many patients ask for further information, including which gene and mutation is involved and what the time to come portends. Here, nosotros confront a dilemma because available data sets do not allow the generation of confident predictions of specific mutations leading to specific changes in later life. It is known that if sun exposure is non avoided, cancer is probable to develop in nearly cases; notwithstanding, if there has been significant sun exposure earlier diagnosis, it is not articulate how the residual DNA damage volition affect afterwards clinical symptoms. In general, most cases of XPC and XPV practice not lead to later neurodegenerative symptoms, but this is non an accented certainty [65,66]. Nearly cases of XPA, XPB, XPD, and XPG do lead to neurodegenerative weather, but not always, and a wide range of disease severity has been reported for a given XP gene due to the specific mutations or genetic backgrounds [25]. Although it might seem reasonable to provide patients with every bit much particular as possible, much of the data gleaned from their Deoxyribonucleic acid sequence may not assist them in terms of healthcare and lifestyle changes; thus, it remains debatable as to what should exist included in a comprehensive diagnostic evaluation.

Acknowledgments

The authors are grateful to several patient support groups, including the XP Gild, Poughkeepsie, NY, Us, the XP Family Support Group, Sacramento, CA, United states of america, and the Luke O'Brien Foundation for Cockayne Syndrome, for their continual back up. The work described here was also supported in part by the National Plant of Neurological Disorders and Stroke grant 1R01NS052781 (JEC) and a program projection grant P01 AR050440-01 (PI: Epstein).

Footnotes

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Disclosure: The author has no other relevant financial interests to disclose.

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