Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells

Significance Faithful genome duplication requires the precise coordination of DNA replication, repair/recombination and chromosome segregation. Homologous recombination (HR) plays a pivotal role in the resumption of blocked replication forks, and HR− cells exhibit both spontaneous slower genome-wide replication fork speed and mitotic extra centrosomes (MECs). We show that MECs result from slow replication kinetics and that MECs are associated with multipolar mitosis leading to general unbalanced chromosome segregation. Thus, low levels of replication stress, which are not detected by cell surveillance, allow cells to progress through the cell cycle, resulting in aberrant mitosis and chromosome instability. These data underline the essential role of HR facing endogenous stress at the interface between replication and mitosis for protection against spontaneous general chromosome instability.