DNA Repair Deficiency Syndromes Research Articles

Assessment of 3 xeroderma pigmentosum group C gene polymorphisms and risk of cutaneous melanoma: a case–control study

Individuals with the rare DNA repair deficiency syndrome xeroderma pigmentosum (XP) are sensitive to the sun and exhibit a 1000-fold increased risk for developing skin cancers, including cutaneous melanoma. Inherited polymorphisms of XP genes may contribute to subtle variations in DNA repair capacity and genetic susceptibility to melanoma. We investigated the role of three polymorphic alleles of the DNA repair gene XPC in a hospital-based case-control study of 294 Caucasian patients from Germany who had cutaneous melanoma and 375 healthy cancer-free sex-matched Caucasian control subjects from the same area. We confirmed that the XPC intron 9 PAT+, intron 11 -6A, and the exon 15 2920C polymorphisms are in a linkage disequilibrium. Only 1.6% of the 669 donors genotyped were discordant for these three polymorphisms. The allele frequencies (cases: controls) were for intron 9 PAT+ 41.7%:36.9%, for intron 11 -6A 41.8%:37.0% and for exon 15 2920C 41.3%:37.3%. Using multivariate logistic regression analyses to control for age, skin type and number of nevi, the three polymorphisms were significantly associated with increased risks of melanoma: OR 1.87 (95% CI: 1.10-3.19; P = 0.022), OR 1.83 (95% CI: 1.07-3.11; P = 0.026), and OR 1.82 (95% CI: 1.07-3.08; P = 0.026), respectively. Exploratory multivariate analyses of distinct subgroups revealed that these polymorphisms were associated with increased risks for the development of multiple primary melanomas (n = 28). The results of our case-control study support the hypothesis that the intron 9 PAT+, intron 11 -6A and exon 15 2920C haplotype may contribute to the risk of developing cutaneous melanoma by increasing the rate of an alternatively spliced XPC mRNA isoform that skips exon 12 and leads to reduced DNA repair. Our results should be validated in independent samples in order to guard against false positive findings.

Mechanisms of human DNA repair: an update.

The human genome, comprising three billion base pairs coding for 30000-40000 genes, is constantly attacked by endogenous reactive metabolites, therapeutic drugs and a plethora of environmental mutagens that impact its integrity. Thus it is obvious that the stability of the genome must be under continuous surveillance. This is accomplished by DNA repair mechanisms, which have evolved to remove or to tolerate pre-cytotoxic, pre-mutagenic and pre-clastogenic DNA lesions in an error-free, or in some cases, error-prone way. Defects in DNA repair give rise to hypersensitivity to DNA-damaging agents, accumulation of mutations in the genome and finally to the development of cancer and various metabolic disorders. The importance of DNA repair is illustrated by DNA repair deficiency and genomic instability syndromes, which are characterised by increased cancer incidence and multiple metabolic alterations. Up to 130 genes have been identified in humans that are associated with DNA repair. This review is aimed at updating our current knowledge of the various repair pathways by providing an overview of DNA-repair genes and the corresponding proteins, participating either directly in DNA repair, or in checkpoint control and signaling of DNA damage.

Xeroderma Pigmentosum: Mondscheinkinder

Das Krankheitsbild des Xeroderma Pigmentosum beruht auf einem Gendefekt im DNS‐Reparatursystem und manifestiert sich bereits in der frühen Kindheit. Beim Xeroderma Pigmentosum handelt es sich um eine seltene autosomal rezessive Genodermatose. Klinisch zeigen diese Kinder eine starke Sonnenempfindlichkeit. Patienten mit Xeroderma Pigmentosum entwickeln schwere Sonnenbrände mit der Ausbildung einer Poikilodermie in lichtexponierter Haut. Bereits in der Kindheit entwickeln sich spinozelluläre Karzinome, Basaliome und maligne Melanome. Die Mehrzahl der Patienten versterben vor dem Erreichen des Erwachsenenalters aufgrund metastasierender kutaner Malignome. Genetisch wird das Xeroderma Pigmentosum in 7 Komplementationsgruppen (XP‐A bis XP‐G) und die Xeroderma‐Pigmentosum‐Variante (XP‐V) unterteilt. Diagnostisch erfolgt die Zuordnung in die jeweilige Komplementationsgruppe durch Fusionierung von Xeroderma‐Pigmentosum‐Fibroblasten. Differentialdiagnostisch muß das Xeroderma Pigmentosum von anderen sogenannten DNS‐Reparatur‐Defizienz‐Syndromen wie dem Cockayne‐Syndrom und der Trichothiodystrophie abgegrenzt werden. Aktuell wird über eine erfolgreiche Anwendung eines topisch applizierten DNS‐Reparatur‐Enzyms berichtet. Hierbei handelt es sich um eine rekombinante liposomal verkapselte T4‐Endonuklease V, welche UV‐induzierte Cyclobutan‐Pyrimidin‐Dimere repariert. In Zukunft könnte eine kausale Behandlung auf der Gentherapie basieren. Das Einschleusen eines intakten Reparaturgens, welches spezifisch das Reparaturprotein kodiert, könnte neue Möglichkeiten der Behandlung des Xeroderma Pigmentosum eröffnen.

Sunscreens and the photodermatoses

The photodermatoses are defined by their clinical features which result from exposure to ultraviolet radiation or visible light. Accurate diagnosis, which is often complicated, is essential to ensure appropriate treatment and protection from precipitating wavelengths. We review the acquired photodermatoses including polymorphic light eruption, hydroa vacciniforme and chronic actinic dermatitis. The genodermatoses including the DNA repair deficiency and melanin-deficient syndromes are discussed, and the best methods for protection of the cutaneous photodermatoses including relevant sunscreen use are elaborated. ( J Dermatol Treat (2001) 12: 53-57)

Influence of environmental and genetic factors on variation in human response to DNA damaging agents

Exogenous DNA damaging agents must be considered in the context of endogenous reactive species which have the potential to damage DNA. Although a no-effect level for a DNA-damaging compound may not exist, it may be feasible to define a level where reducing exposure to the compound is no longer the most effective way of reducing human risk. Modifying environmental factors which affect human response to damage may be the better strategy. Although a number of rare human syndromes are associated with a reduced ability to repair DNA damage, it is not clear how wide is the range of genetic variation in repair capacity among normal individuals. Studies with DNA repair-deficient human syndromes indicate that processes other than mutation and DNA repair must be involved in the development of cancer, and these processes may represent new sources of variation in human response to genotoxic agents.

Somatic cell mutation frequency at the HPRT, T-cell antigen receptor and glycophorin A loci in Cockayne syndrome

Skin fibroblasts of patients with Cockayne syndrome (CS) are hypersensitive to the lethal or mutagenic effect of ultraviolet light, which may cause genetic instability. Up to now, however, no systematic study of in vivo somatic cell mutation in CS cells has been reported. This article describes our investigation of the mutation frequencies (Mfs) at three different loci, i.e. hypoxanthine-guanine phosphoribosyl transferase (HPRT), T-cell antigen receptor (TCR) and glycophorin A (GPA), in six patients with CS. Mfs at the HPRT and TCR loci were found to be within the normal range as determined in age-matched controls. In the GPA locus of two patients, there was a slight increase, but it was much smaller than that reported in other DNA repair deficient syndromes. The frequency of spontaneous HPRT mutation in Epstein-Barr virus transformed B-lymphoblastoid cells derived from CS patients was similar to that in cells from normal children. The molecular characterization of the representative HPRT mutant T cell clones from CS patients did not show any structural alterations. These results may explain, at least in part, why CS is not associated with predisposition to cancer.

The genetic defect in DNA repair deficiency syndromes: EACR—Mühlbock Memorial Lecture, 1993

The genetic defect in DNA repair deficiency syndromes: EACR—Mühlbock Memorial Lecture, 1993

Flowcytometric Analysis of DNA Pattern of Cells Derived from Xeroderma Pigmentosum A– Hypersensitivity to Vincristine, Etoposide and Methotrexate–

Xeroderma pigmentosum complementation group A (XPA) is one of the DNA repair deficient syndromes. The cell biological features of XPA were examined by flowcytometry using Epstein Barr (EB) virus-transformed lymphoblastoid cells. Cellular sensitivity to vincristine (VCR), etoposide (VP-16) and methotrexate (MTX) were assayed by DNA pattern changes by flowcytometry. Recently, ataxia-telangiectasia (AT), one of the same kind of disorder, has been reported to have an increased sensitivity to VCR and VP-16. However, AT showed some resistance to MTX according to other reports. Our results showed that XPA had an increased sensitivity to VCR and also to VP-16. Moreover, different from AT, XPA showed some sensitivity to MTX. Thus there is some cell biological similarity between XPA and AT, as well as some difference of the abnormality in the DNA repair pathway.

Mechanisms and Consequences of Mutation Induction in Mammalian Cells

Mutations have been studied for several decades in order to understand biological processes of great significance and the selection of better-adapted species. Our knowledge both of mutation spectra induced by genotoxic agents and the mechanisms involved in DNA damage processing is more advanced in bacteria than in animal cells. However, the use of new technologies such as shuttle vectors or the polymerase chain reaction will undoubtedly allow rapid progress in the next few years. Shuttle vectors consist of target sequences for monitoring mutagenic activity and additional sequences permitting DNA replication and selection, both in bacteria and in mammalian cells. These plasmids are very efficient in allowing the production of mutation spectra of a particular genotoxin in animal cells. In most cases, base substitutions occur predominantly at the sites of base damage and the type of substitution depends on the kind of damage. This has been well characterized using ultraviolet (UV) light as a mutagen. UV-induced mutations are targeted opposite pyrimidine-pyrimidine sites, where the two major UV lesions are produced. The direct relationships existing between mutation and cancer are exemplified by some hereditary diseases where deficiency in an enzymatic repair system is linked to a high incidence of tumours. Similarly, activation of some cellular proto-oncogenes occurs via specific point mutations. A correlation does exist between the mutation spectra found in model systems and the specific mutation found in the activated oncogene in tumours induced by a given genotoxin. This is particularly well illustrated in the DNA repair deficiency syndrome, xeroderma pigmentosum. The specific mutations found in activated ras oncogenes isolated from UV-stimulated skin tumours correlate well with the mutagenic properties of unrepaired UV-induced DNA lesions.

Genome instability and DNA repair deficiency syndromes - links with cancer : B.A. Bridges, MRC Cell Mutation Unit, University of Sussex, Falmer, Brighton BN1 9QG, England

Genome instability and DNA repair deficiency syndromes - links with cancer : B.A. Bridges, MRC Cell Mutation Unit, University of Sussex, Falmer, Brighton BN1 9QG, England

Genetic effects on the longevity of cultured human fibroblasts. III. Correlations with altered glucose-6-phosphate dehydrogenase.

The level of heat-labile glucose-6-phosphate dehydrogenase (G6PD) has been measured in skin fibroblast cultures from premature ageing or DNA repair deficient genetic syndromes. The short in vitro longevity of Werner's syndrome, progeria, Cockayne's syndrome, ataxia telangiectasia, Fanconi's anaemia, and Bloom's syndrome cultures was correlated with the appearance of a significant fraction of heat-labile enzyme. Long-lived control cultures contain a low level of altered enzyme until they become senescent. The evidence that heat-labile G6PD molecules are derived from errors in synthesis, or from other causes, is critically assessed. It is shown that normal cells grown in medium containing the antibiotic, paromomycin, which is known to reduce the fidelity of ribosomal translation, produce a significant fraction of altered G6PD.