Under-Replicated DNA: The Byproduct of Large Genomes?

SIMPLE SUMMARY: Higher eukaryotic cells frequently enter mitosis with a certain load of under-replicated DNA, also referred to as unreplicated DNA, due to incomplete genomic DNA replication during the previous S phase. Double replication fork stalling events, when two converging forks irreversibly stall with no replication origin in between them, seem to be one of the major drivers of incomplete genomic replication in S phase. Genome stability is yet maintained in the vast majority of cells implying that cells must possess dedicated post-replicative mechanisms that allow for faithful repair of these seemingly unavoidable errors. Here, we provide a comprehensive overview of the mechanisms or events that cause, regulate and repair under-replicated DNA in eukaryotic cells. ABSTRACT: In this review, we provide an overview of how proliferating eukaryotic cells overcome one of the main threats to genome stability: incomplete genomic DNA replication during S phase. We discuss why it is currently accepted that double fork stalling (DFS) events are unavoidable events in higher eukaryotes with large genomes and which responses have evolved to cope with its main consequence: the presence of under-replicated DNA (UR-DNA) outside S phase. Particular emphasis is placed on the processes that constrain the detrimental effects of UR-DNA. We discuss how mitotic DNA synthesis (MiDAS), mitotic end joining events and 53BP1 nuclear bodies (53BP1-NBs) deal with such specific S phase DNA replication remnants during the subsequent phases of the cell cycle.