title: Rif1 regulates the replication timing domains on the human genome.
abstract: DNA replication is spatially and temporally regulated during S-phase. DNA replication timing is established in early-G1-phase at a point referred to as timing decision point. However, how the genome-wide replication timing domains are established is unknown. Here, we show that 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. Depletion of Rif1 results in specific loss of mid-S replication foci profiles, stimulation of initiation events in early-S-phase and changes in long-range replication timing domain structures. Analyses of replication timing show replication of sequences normally replicating early is delayed, whereas that normally replicating late is advanced, suggesting that replication timing regulation is abrogated in the absence of Rif1. 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. Our results indicate that Rif1 plays crucial roles in determining the replication timing domain structures in human cells through regulating higher-order chromatin architecture.
authors: Genome Dynamics Project, Department of Genome Medicine, Tokyo, Japan.
authors: Satoshi
authors: S
authors: Yamazaki
authors: Aii
authors: A
authors: Ishii
authors: Yutaka
authors: Y
authors: Kanoh
authors: Masako
authors: M
authors: Oda
authors: Yasumasa
authors: Y
authors: Nishito
authors: Hisao
authors: H
authors: Masai
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D015894:Genome, Human; D006367:HeLa Cells; D006801:Humans; D008957:Models, Genetic; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D016196:S Phase; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; C492743:Rif1 protein, human; D034501:Telomere-Binding Proteins; D004247:DNA; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases