Abstract
SummaryDNA replication is temporally and spatially organized in all eukaryotes, yet the molecular control and biological function of the replication-timing program are unclear. Rif1 is required for normal genome-wide regulation of replication timing, but its molecular function is poorly understood. Here we show that in mouse embryonic stem cells, Rif1 coats late-replicating domains and, with Lamin B1, identifies most of the late-replicating genome. Rif1 is an essential determinant of replication timing of non-Lamin B1-bound late domains. We further demonstrate that Rif1 defines and restricts the interactions between replication-timing domains during the G1 phase, thereby revealing a function of Rif1 as organizer of nuclear architecture. Rif1 loss affects both number and replication-timing specificity of the interactions between replication-timing domains. In addition, during the S phase, Rif1 ensures that replication of interacting domains is temporally coordinated. In summary, our study identifies Rif1 as the molecular link between nuclear architecture and replication-timing establishment in mammals.
Highlights
The eukaryotic genome is organized into domains whose replication follows a cell-type distinctive temporal order that is defined when the associated replication origins are activated during the S phase
Rif1 is required for normal genomewide regulation of replication timing, but its molecular function is poorly understood
Rif1 is an essential determinant of replication timing of non-Lamin B1bound late domains
Summary
The eukaryotic genome is organized into domains whose replication follows a cell-type distinctive temporal order that is defined when the associated replication origins are activated during the S phase (reviewed in Rhind and Gilbert, 2013). Several origin-binding DNA replication factors are available in limiting amounts Their interaction either promotes or antagonizes the activation of the loaded helicases at each origin and determines the probability, and the order, of firing (Mantiero et al, 2011; Patel et al, 2006; Tanaka et al, 2011; Wu and Nurse, 2009). These findings demonstrate that the execution of the DNA replication-timing (RT) program is controlled at the level of individual origins during the S phase. The establishment of the RT program is independent of the individual
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