Rif1 choreographs DNA replication timing.
چکیده
Eukaryotic cells duplicate their genome in a predetermined order that appears to reflect a fundamental property of chromatin. Each chromosomal region replicates at a consistent, developmentaland tissue-specific time during the S phase of the cell cycle, and regions that replicate at the same time form distinct patterns in threedimensional nuclear space. Although orderly progression of DNA replication is important for insuring stable genetic and epigenetic inheritance, the mechanisms underlying replication patterns have yet to be elucidated. Two reports in The EMBO Journal now identify a protein, Rif1, as a novel global determinant of the mammalian DNA replication program, and provide a link between higher order chromatin assembly and proper cell-cycle progression. Shortly after cell division, cells organize their genomes into large (41Mb) ‘replication domains’ containing multiple replication initiation sites that replicate at the same time, share distinct chromatin conformations and localize to discrete chromatin-interaction compartments (Hiratani et al, 2009; Ryba et al, 2010; Yaffe et al, 2010). Replication domain organization occurs during the G1 phase of the cell cycle at the so-called timing decision point, coincident with chromosome positioning. Early replicating chromatin primarily resides internally in the nucleus, commonly exhibits a decondensed (‘open’) conformation and includes active genes. Latereplicating chromatin resides in the nuclear periphery, is often densely packaged and primarily contains transcriptionally inactive genomic regions. During differentiation, transcriptional silencing frequently correlates with replication delay and transcriptional activation correlates with advanced replication timing (Hiratani et al, 2009; Eaton et al, 2011). The division into replication timing domains and the tissue specificity of replication timing exhibits high evolutionary conservation in syntenic regions (Ryba et al, 2010; Yaffe et al, 2010). Evolutionary conservation of replication patterns might reflect a role for distinct temporal and spatial order of replication in facilitating epigenetic inheritance by insuring correct packaging of DNA after replication. For example,