Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum C

Abstract

Xeroderma pigmentosum (XP), a UV-sensitivity syndrome characterized by skin hyperpigmentation, premature aging, and increased skin cancer, is caused by defects in the nucleotide excision repair (NER) pathway. XP shares phenotypical characteristics with telomere-associated diseases like Dyskeratosis congenita and mouse models with dysfunctional telomeres, including mice deficient for telomerase (Terc À/À mice). Thus, we investigated a hypothesized role for telomerase and telomere dysfunction in the pathobiology of XP by comparing Xpc-mutant mice and Xpc À/À G1-G3Terc À/À double-mutant mice and exposed them to UV radiation.Chronically UV-exposed Xpc À/À skin displayed shorter telomeres on an average compared with wild-type skin.Strikingly, this effect was reversed by an additional deficiency in the telomerase. Moreover, aberrantly long telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase suggested activation of the alternative lengthening of telomeres (ALT) in the UV-exposed skin of the double mutants. Mechanistic investigations revealed an elevated susceptibility for UV-induced p53 patches, known to represent precursor lesions of carcinomas, in Xpc À/À G1-G3Terc À/À mice where a high number of UV-induced skin tumors occurred that were characterized by aggressive growth. Taken together, our results establish a role for xeroderma pigmentosum, complementation group C (XPC) in telomere stability, particularly upon UV exposure. In absence of telomerase, critically short telomeres in XP mutants seem to aggravate this pathology, associated with an increased tumor incidence, by activating the ALT pathway of telomere lengthening. Cancer Res; 73(6);

Impact of sperm DNA damage and oocyte-repairing capacity on trout development

“…Tolerance to damage, suppressing the induction of apoptosis, is a known mechanism allowing to progress with development in stressful environmental conditions, as was observed in corals (Tchernov et al 2011) or in rainbow trout embryos with inhibited repairing machinery (Fernandez-Diez et al 2015). tp53 in fish is very similar to mammalian TP53, and is highly and ubiquitously expressed in zebrafish early embryos (Storer & Zon 2010). As reviewed by Liu and colleagues (2011), fish tp53 is functionally similar to mammalian TP53, being regulated by MDM2 and regulating the transcription of the same genes that drive to apoptosis.…”

“…We have observed that oocytes collected out of season showed a significant increase in all the analyzed repair transcripts (up to 9.15 times in rad1mRNA) except in tp53 mRNA which was downregulated. The analyzed transcripts are involved in DNA damage control and the repair of different kind of lesions could be promoted during gametogenesis: ogg1 is involved in the removal of 8-oxoguanyne, mutagenic base produced after ROS (Gagne et al 2013); DNA lig3 plays a crucial role in the repairing of DNA single-strand breaks during embryo development and cannot be replaced by any other DNA ligase (Puebla-Osorio et al 2006); ung gene encodes for uracil-DNA glycosylase which is involved in excision of uracil residues from U:G and U:A mispairs in DNA molecule, participating in BER pathway -recent reports in zebrafish have demonstrated its implication in a correct embryo development during post-fertilization (Wu et al 2014); rad1 mRNA encodes Rad1, checkpoint protein which is involved in cell cycle arrest (Bozdarov et al 2013), playing an important role during the correct embryo development (Han et al 2010); and tp53 is one of the most important transcriptional factors with suppressive and proapoptotic functions upon genotoxic stress (Storer & Zon 2010). The expression of tp53 is usually enhanced under conditions of genomic instability.…”

“…As reviewed by Liu and colleagues (2011), fish tp53 is functionally similar to mammalian TP53, being regulated by MDM2 and regulating the transcription of the same genes that drive to apoptosis. Zebrafish knockdown for tp53 is developmentally normal in homeostatic conditions, but displays a reduced induction of apoptosis after genotoxic damage (Duffy & Wickstrom 2007, Storer & Zon 2010. This effect was observed in a late stage, at organogenesis, the apoptotic activity being clearly reduced in LRS batches.…”

XPC: Going where no DNA damage sensor has gone before

“…Linking XPC to chromosomal stability, Xpc −/− primary mouse embryonic fibroblasts exhibit augmented characteristics of telomere instability compared to wild-type cells including an increased number of telomere sister chromatid exchanges, chromosome-type fusions, and multitelomeric signals (MTS). While the already augmented levels of MTS in Xpc −/− cells increase further in response to several cellular stressors, hypoxic conditions in Xpc −/− cells actually lead to diminished levels of MTS, similar to the typical levels observed in Xpc +/+ cells [74]. Although the authors argue that telomere fragility in Xpc −/− cells is linked to increased sensitivity to oxidative damage, sensitivity to conditions whose telomere fragility can be repaired in Xpc +/+ cells yet not in Xpc −/− cells could be lauded as more indicative of XPC function.…”

Sequential release of salidroside and paeonol from a nanosphere-hydrogel system inhibits ultraviolet B-induced melanogenesis in guinea pig skin

“…Using this system, the intention was to provide burst release of salidroside from the hydrogel, which would rapidly inhibit synthesis of melanin in response to irritation by UVB, followed by continuous elimination of melanin by the paeonol released in a sustained manner from the nanospheres. The efficacy of this dual drugreleasing nanosphere-hydrogel in decreasing and preventing melanogenesis was investigated using the UVB-irradiated melanogenesis skin model, 32,33 with single drug-loaded preparations serving as controls.…”