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    • Inefficient DNA DSB repair can promote genomic rearrangement

    2018-10-20

    Inefficient DNA DSB repair can promote genomic rearrangements which can lead to malignant transformations (Reya et al., 2001) thus leading to the notion that stem cells with compromised genome integrity commit altruistic suicide or differentiate, and are more sensitive to DNA damage than other cells. However, hair-follicle-bulge stem cells are resistant to DNA damage-induced apoptosis, largely mediated by higher expression of anti-apoptotic Bcl-2 (Sotiropoulou et al., 2010). Moreover, highly enriched hematopoietic stem and progenitor cells (HSPCs) express more anti-apoptotic genes (but not Bcl-2) and less pro-apoptotic genes (but not Bim) than myeloid progenitors (Mohrin et al., 2010). In a context of reduced apoptosis, proficient and accurate DSB repair is necessary to assure that survivor cells do not incur genome instability and deleterious mutations (Chapman et al., 2012). Interestingly, hair-follicle-bulge stem cells display a faster DNA repair than other basal epidermal cells (Sotiropoulou et al., 2010). HSPC cells also display efficient DSB repair but this is frequently associated with genome rearrangements (Mohrin et al., 2010). Adult stem cells and their derived tissues display different sensitivities to radiation-induced DNA damage (Blanpain et al., 2011), suggesting that they might respond differently to genotoxic injury. Unresolved questions include whether other stem cells are simultaneously more apoptosis-resistant and DNA repair prone than differentiated cells, and whether a high occurrence of mutations is the necessary output for efficient DSB repair in stem cells. Differences in repair efficiency and accuracy could be ascribed to distinct repair mechanisms associated with Tubastatin A HCl phase. Proliferating cells rely essentially on accurate recombination-dependent repair (HR, homologous recombination), acting mostly during S/G2 (Chapman et al., 2012). In contrast, non-dividing cells rely essentially on non-homologous end-joining (NHEJ), which is active during the entire cell cycle. NHEJ joins the broken ends and displays some inaccuracy depending on the type of DNA ends (Wyman and Kanaar, 2006). In agreement with this notion, quiescent HSPCs express lower levels of HR-associated repair factors and higher levels of NHEJ markers than proliferating HSPCs (Mohrin et al., 2010). Skeletal muscle growth and regeneration are mediated by satellite (stem) cells that have robust regenerative potential and are quiescent in the adult. After muscle injury, they enter the cell cycle and produce myoblasts that fuse to effect muscle regeneration. Satellite cells subsequently self-renew in their niche, which is located between the myofiber plasmalemma and the basement membrane. Transcription factors including the homeobox/paired domain gene Pax7, the myogenic determination genes Myf5 and Myod, and the differentiation gene Myogenin play critical roles in satellite cell regulation (Relaix and Zammit, 2012; Tajbakhsh, 2009). The well-defined stages of lineage progression as well as markers and morphological readouts for distinguishing the distinct cell states from stem to differentiated cells provide an ideal system to investigate how stem cells and their progeny in this tissue respond to IR-induced genotoxic stress. Previous studies showed that high-doses of irradiation (18–25Gy) compromise satellite cell function and muscle regeneration (Boldrin et al., 2012; Gayraud-Morel et al., 2009; Gross and Morgan, 1999; Heslop et al., 2000; Pagel and Partridge, 1999; Wakeford et al., 1991). Muscle regeneration in response to genotoxic stress is affected by a variety of factors, as muscle damage rescues proliferation of some myogenic cells after high doses of limb irradiation (Gross and Morgan, 1999; Heslop et al., 2000). Moreover, preservation of the niche has a key role in muscle regeneration during engraftment (Boldrin et al., 2012), which is also significantly affected by non-myogenic cells like macrophages (Saclier et al., 2013b). Regeneration in normal and irradiated muscle relies on multiple cell types and cell–cell signaling, however the relative contribution of these cells remains unknown. Therefore a systematic analysis of each cell type is critical to understand how regeneration occurs after irradiation. Here, we show that skeletal muscle stem cells exhibit a robust DNA repair machinery, and that they perform IR-induced DSB repair significantly better than their committed progeny, and with a higher accuracy. Further, the proliferation status of cells appears to affect the repair efficiency to a lower extent than does differentiation. Finally, we show that the niche does not significantly affect the repair efficiency of muscle stem cells pointing to a cell autonomous role for DNA repair.