Abstract
Duplicating a genome of 3 billion nucleotides is challenged by a variety of obstacles that can cause replication stress and affect the integrity of the genome. Recent studies show that replication fork slowing and stalling is prevalent in early mammalian development, resulting in genome instability and aneuploidy, and constituting a barrier to development in human reproduction. Genome instability resulting from DNA replication stress is a barrier to the cloning of animals and to the reprogramming of differentiated cells to induced pluripotent stem cells, as well as a barrier to cell transformation. Remarkably, the regions most impacted by replication stress are shared in these different cellular contexts, affecting long genes and flanking intergenic areas. In this review we integrate our knowledge of DNA replication stress in mammalian embryos, in programming, and in reprogramming, and we discuss a potential role for fragile sites in sensing replication stress and restricting cell cycle progression in health and disease.