question: How does Rif1 regulate DNA replication?
answer: Rif1 (Rap1-interacting-factor-1), originally identified as a telomere-binding factor in yeast, is a critical determinant of the replication timing programme in human cells. Rif1 tightly binds to nuclear-insoluble structures at late-M-to-early-G1 and regulates chromatin-loop sizes. Furthermore, Rif1 colocalizes specifically with the mid-S replication foci. Thus, Rif1 establishes the mid-S replication domains that are restrained from being activated at early-S-phase. Overall, Rif1 plays crucial roles in determining the replication timing domain structures in human cells through regulating higher-order chromatin architecture. This function of Rif1 depends on its interaction with PP1 phosphatases and the PP1/Rif1 interaction is downregulated by the phosphorylation of Rif1, most likely by CDK/DDK.