Role of cell cycle control, checkpoints, and DNA repair mechanisms in stem cells and changes with aging and cancerogenesis

Abstract

The regulation of cell cycle progression, checkpoint activation, and DNA repair in stem cells is distinct from the regulation in progenitors and differentiated cells. For a broad range of types of stem cells, such as embryonic, muscle, and hematopoietic stem cells, these mechanisms have already been described. Either a complete absence or corrupted activity of checkpoints such as the G1/S damage response and the decatenation checkpoint was found or strong alterations in DNA repair mechanisms could be identified. Moreover, stem cells also activate their own distinct checkpoints, such as the novel differentiation checkpoint. It is currently not completely understood why stem cells maintain these distinct regulatory checkpoints and how they contribute to tissue homeostasis, stem cell function, and genome integrity. Furthermore, it is unclear how these mechanisms change upon aging and whether alterations in them significantly contribute to the transformation process and the development of diseases, such as MDS and leukemia. The following chapter will provide a general overview of cell cycle control, checkpoint activity, and DNA repair mechanisms in hematopoietic and other adult stem cells as well as progenitor cells and their relevance for genome integrity, homeostasis, aging, and disease. We will further highlight checkpoint proteins as potential pharmaceutical targets to treat age-related diseases.