Rif1-Dependent Regulation of Genome Replication in Mammals

Eukaryotic genomes are replicated starting from multiple origins of replication. Their usage is tightly regulated, and not all the potential origins are activated during a single cell cycle. In addition, the ones that are activated are activated in a sequential order. Why don't origins of replication normally all fire together? Is this important? And if so, why? Would any order of firing do, or does the specific sequence matter? How is this process regulated? These questions concern all eukaryotes but have proven extremely hard to address because replication timing is a process intricately connected with multiple aspects of nuclear function.