Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death

Abstract

Adult stem cells (SCs) are at high risk of accumulating deleterious mutations because they reside and self-renew in adult tissues for extended periods. Little is known about how adult SCs sense and respond to DNA damage within their natural niche. Here, using mouse epidermis as a model, we define the functional consequences and the molecular mechanisms by which adult SCs respond to DNA damage. We show that multipotent hair-follicle-bulge SCs have two important mechanisms for increasing their resistance to DNA-damage-induced cell death: higher expression of the anti-apoptotic gene Bcl-2 and transient stabilization of p53 after DNA damage in bulge SCs. The attenuated p53 activation is the consequence of a faster DNA repair activity, mediated by a higher non-homologous end joining (NHEJ) activity, induced by the key protein DNA-PK. Because NHEJ is an error-prone mechanism, this novel characteristic of adult SCs may have important implications in cancer development and ageing.

Pygo2 regulates β-catenin–induced activation of hair follicle stem/progenitor cells and skin hyperplasia

“…6). Although addressing these issues lies outside the scope of this study, several reports support the latter notion: p53 protein is stabilized in the skin epithelium following irradiation and loss of Brca1 (38,39), and p53 ablation in mice where Atr is deleted locally in skin causes a severe delay in depilation-induced HF regeneration due to accumulation of too many damaged cells (40). Most importantly, our results demonstrate that (i) the quiescence-to-proliferation transition of HF SC/EPCs in vivo resembles cultured cells that receive mitogenic stimuli in mounting a p53 response and (ii) β-catenin and Pygo2 act together to induce this response in epidermal stem/progenitor cells.…”

p53/p63/p73 in the Epidermis in Health and Disease

“…Both cell populations are slow cycling and survive chemotherapy, and their protection against DNA damage is mediated, at least in part, by high levels of expression of the antiapoptotic Bcl2 protein that blocks p53-dependent apoptosis (Lindner et al 1997;Sotiropoulou et al 2010). In addition to Bcl2, protection of bulge stem cells against ionizing radiation is mediated by high activity of the DNA repair machinery including DNA-PK (Sotiropoulou et al 2010).…”

Raman micro spectroscopy study of the interaction of vincristine with A549 cells supported by expression analysis of bcl-2 protein

“…40 Interestingly, in comparison to the effects on the nuclear Raman spectrum as a result of exposure to cisplatin, a known DNA groove binder, 2 , the changes observed in the conformation of the B-form of DNA, the dominant form of cellular DNA, are more prominent. These changes, 45 including decreases in the Raman intensities of the bands due to DNA bases and changes in the DNA conformation are the important Raman markers of DNA intercalation 33,[35][36][37] . Changes in the phosphodiester linkages, the O-P-O stretching vibrations of the DNA, are also observed at 50 1095 cm -1 along with a shift towards lower wavenumber at the higher concentrations including 3 and 10 μM.…”

“…Cancer cell lines can be a 40 good model to study the effects of these anticancer agents and such in vitro studies are in accordance with the EU policy of Reduction, Replacement and Refinement (RRR) of the protection of animals used for experimental and scientific purposes (Directive 2010/63/EU). Another 45 concern is the requirement of a non-invasive, cost effective, rapid screening technique which can analyse the samples, ideally without any labelling. Raman micro spectroscopy potentially provides these benefits 1 .…”