Figure 6. scanning electron microscopy. (Upper left) Grooved, irregular hair surface. (Upper right) Flattened hair, resulting in a ribbon-like appearance. (Lower left) Trichorrhexis nodosa-like fracture. (Lower right) Trichoschisis. The original magnification in millimeters is indicated by the length of the row of dots (adapted from Liang et al., 2006).

UV-induced skin cancers comprise a major problem in organ transplant recipients (OTRs). Cyclosporin A, a calcineurin inhibitor, is used as a standard immunosuppressant and clearly increases the skin cancer risk. Azathioprine does not appear to result in such an increase in skin cancer risk, and mTOR inhibitors are associated with an even lesser skin cancer risk. The underlying molecular mechanisms of these clinically important differences among immunosuppressants are still unclear and may relate to other than immunological effects. Insights may be gained by the multistep skin cancer theory and xeroderma pigmentosum, where defective nucleotide excision repair (NER) results in a cellular mutator phenotype and cutaneous carcinogenesis. This viewpoint assay summarizes current knowledge about the influence of the most commonly used immunosuppressive drugs in OTRs on DNA repair. Calcineurin inhibition results in a 200-fold increased skin cancer risk compared with the normal population and inhibits NER. The skin cancer risk under azathioprine is threefold less compared with calcineurin inhibitors, which may relate to inhibition of only the last step of NER, i.e. gap filling. mTOR inhibitors do not reduce NER in the global genome and can inhibit the growth of already initiated tumors, which may account for the markedly reduced skin cancer risk compared with calcineurin inhibitors. We conclude that OTRs may benefit from treatment regimens other than calcineurin inhibitors and speculate that a targeted modulation of calcineurindependent signalling may prevent UV-induced tumor formation by enhancing NER not only in OTRs but also in the general population, at least in part.

Genomic instability is the driving force behind cancer development. Human syndromes with DNA repair deficiencies comprise unique opportunities to study the clinical consequences of faulty genome maintenance leading to premature aging and premature cancer development. These syndromes include chromosomal breakage syndromes with defects in DNA damage signal transduction and double-strand break repair, mismatch repair defective syndromes as well as nucleotide excision repair defective syndromes. The same genes that are severely affected in these model diseases may harbour more subtle variations in the 'healthy' normal population leading to genomic instability, cancer development, and accelerated aging at later stages of life. Thus, studying those syndromes and the molecular mechanisms behind can significantly contribute to our understanding of (skin) cancerogenesis as well as to the development of novel individualized preventive and therapeutic anticancer strategies. The establishment of centers of excellence for studying rare genetic model diseases may be helpful in this direction.

About 12% of human genetic disorders involve premature termination codons (PTCs). Aminoglycoside antibiotics have been proposed for restoring full-length proteins by readthrough of PTC. To assess the efficiency of readthrough, we selected homozygous and compound heterozygous skin fibroblasts from xeroderma pigmentosum (XP) patients with different PTCs in the XPC DNA repair gene. XP patients have a nucleotide excision repair defect and a 10,000-fold increased risk of UV-induced skin cancer. In six of eight PTC-containing XP-C cells, treatment with Geneticin and gentamicin resulted in (i) stabilized XPC-mRNA, which would have been degraded by nonsense-mediated decay; (ii) increased expression of XPC protein that localized to UV-damaged sites; (iii) recruitment of XPB and XPD proteins to UV DNA damage sites; and (iv) increased repair of 6-4 photoproducts and cyclobutane pyrimidine dimers. Expression of PTC in a transfected vector revealed that readthrough depends on the PTC sequence and its location within the gene. This sensitive DNA repair assay system demonstrates the complexity of response to PTC readthrough inducers. The efficiency of aminoglycoside-mediated readthrough depends on the type and copy number of PTC, the downstream 4+ nucleotide, and the location within the exon. Treatment with small-molecule nonaminoglycoside compounds (PTC124, BZ16, or RTC14) resulted in similarly increased XPC mRNA expression and photoproduct removal with less toxicity than with the aminoglycosides. Characterizing PTC structure and parameters governing effective PTC readthrough may provide a unique prophylactic therapy for skin cancer prevention in XP-C patients.readthrough compounds | UV radiation