Nuclear organisation and replication timing are coupled through RIF1-PP1 interaction

Parallels between three-dimensional genome organisation and replication timing suggests the hypothesis of their possible interdependence. However, it remains unknown whether nuclear architecture overall plays an instructive role in the replication-timing program. Here we demonstrate that they are coupled through RIF1, the molecular hub that co-regulates both processes. Both nuclear organisation and replication timing depend upon the interaction between RIF1 and PP1. However, whereas nuclear architecture requires the full complement of RIF1 and its interaction with PP1, replication timing is not sensitive to RIF1 dosage. RIF1’s role in replication timing also extends beyond its interaction with PP1. Availing of this separation-of-function approach, we have therefore identified the molecular bases of the co-dependency of the replication-timing program and nuclear architecture.