Stem cell quiescence requires PRC2/PRC1-mediated mitochondrial checkpoint

Both normal and tumorous stem cells can arrest cell division, avoid apoptosis, and then regenerate lost daughter cells following acute genotoxic insult. This protective, reversible proliferative arrest, known as 'quiescence,' is still poorly understood. Here, we show that mTOR-regulated mitophagy is required for radiation insult-induced quiescence in Drosophila germline stem cells (GSCs). In GSCs, depletion of mito-fission (Drp1) or mitophagy (Pink1 and Parkin) eliminates entry into quiescence, while depletion of mitochondrial biogenesis (PGC-1alpha;) or fusion (Mfn2) eliminates exit from quiescence. We also find that mitophagy-dependent quiescence is under epigenetic control; knockdown of Jarid2 (PRC2) or Pc or Sce (PRC1) stabilizes the mitochondria and locks GSCs out of quiescence, while knockdown of PRC2-specific demethylase, Utx, prevents re-accumulation of the mitochondria and locks GSCs in quiescence. These data suggest that mitochondrial number coordinates reversible quiescence. We further identify that the mechanism of quiescence in both GSCs and human induced pluripotent stem cells (iPSCs) relies on mitophagy to deplete the mitochondrial pool of CycE and limit cell cycle progression. This alternative method of G1/S regulation may present new opportunities for therapeutic purposes.

Pivotal role for skin transendothelial radio-resistant anti-inflammatory macrophages in tissue repair

Heterogeneity and functional specialization among skin-resident macrophages are incompletely understood. In this study, we describe a novel subset of murine dermal perivascular macrophages that extend protrusions across the endothelial junctions in steady-state and capture blood-borne macromolecules. Unlike other skin-resident macrophages that are reconstituted by bone marrow-derived progenitors after a genotoxic insult, these cells are replenished by an extramedullary radio-resistant and UV-sensitive Bmi1+ progenitor. Furthermore, they possess a distinctive anti-inflammatory transcriptional profile, which cannot be polarized under inflammatory conditions, and are involved in repair and remodeling functions for which other skin-resident macrophages appear dispensable. Based on all their properties, we define these macrophages as Skin Transendothelial Radio-resistant Anti-inflammatory Macrophages (STREAM) and postulate that their preservation is important for skin homeostasis.

Cellular response to the genotoxic insult: the question of threshold for genotoxic carcinogens

Maintenance of cellular integrity is crucial for its physiological function, which is constantly threatened by DNA damage arising from numerous intrinsic and environmental sources.

Post-translational modifications of lysine in DNA-damage repair

DNA damage in cells is often the result of constant genotoxic insult. Nevertheless, efficient DNA repair pathways are able to maintain genomic integrity. Over the past decade it has been revealed that it is not only kinase signalling pathways which play a central role in this process, but also the different post-translational modifications at lysine residues of histone (chromatin) and non-histone proteins. These lysine modifications include acetylation, methylation, ubiquitination and SUMOylation. Genomic instability is often the major cause of different diseases, especially cancer, where lysine modifications are altered and thereby have an impact on the various DNA repair mechanisms. This chapter will discuss the recent advances in our understanding of the role of different lysine modifications in DNA repair and its physiological consequences.