1. Replicating Large Genomes: Divide and Conquer
Juan Carlos Rivera-Mulia, David M. Gilbert 
Molecular Cell 
Volume 62, Issue 5, Pages (June 2016)
DOI: /j.molcel
Copyright © 2016 Elsevier Inc. Terms and Conditions

2. Figure 1
The Distinct Scales of DNA Replication Regulation in Eukaryotes
(A) Replication origin regulation. The origin recognition complex (ORC) binds at all potential replication origins that become licensed by the CDT1-dependent recruitment of MCM-helicase complex (a double hexamer of the subunits MCM2– MCM7) to form the pre-RC. All potential origins are licensed, but only ∼10% are activated. Additional factors are recruited, followed by DDK phosphorylation of distinct residues of the MCM complex that trigger the helicase activity, splitting the MCM hexamers and starting the bidirectional unwinding of the DNA strands. For simplicity, the depiction does not include all components of the pre-RC and pre-IC. For a detailed description, see Yeeles et al. (2015).
(B) DNA replication regulation at the replication domain scale. Synchronized firing of clusters of origins activated either early or late during S phase partitions the chromosomes into replication domains.
(C) DNA replication at the nuclear scale and its regulation during the cell cycle. RDs are segregated within the nucleus in such a way that early replicating segments of the chromosomes occupy the nuclear interior while the late RDs are preferentially located close to the nuclear and nucleolar (N) periphery. Origin licensing occurs only from M to G1, then CDT1 is rapidly degraded and sequestrated by geminin-blocking origin re-licensing, although additional inhibitors might repress pre-RC activation during the G1-S transition (Sasaki et al., 2011). Then an induction of DDK/S-CDK in S phase activates the pre-IC to initiate replication. The timing decision point (TDP) occurs early during G1 and precedes origins selection (ODP).
Molecular Cell  , DOI: ( /j.molcel )
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3. Figure 2
Heterogeneity in Replication Origin Selection and Regulation of Replication Activation under Stress
(A) Multiple potential replication origins are licensed within each RD. Distinct cells within the same population use different origins under normal conditions.
(B) Regulation of origin activation under replication stress. When replication forks are stalled, checkpoint responses are induced to promote the activation of dormant origins within the RD while inhibiting the firing of origins in RDs that are activated later in S phase (Gilbert, 2007).
Molecular Cell  , DOI: ( /j.molcel )
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4. Figure 3 G4s and Replication Origin Specification
(A) G4 structure. Rings of guanine quartets are stacked on top each other and stabilized by hydrogen bonds.
(B) G4s might cooperate with additional cis elements (such as NFRs or AT-rich regions) to specify the more efficient location of replication initiation (modified from Valton et al., 2014).
(C) Gene expression can influence origin selection by generating R-loops that enhance G4 formation or “push” the pre-RC toward G4 motifs.
Molecular Cell  , DOI: ( /j.molcel )
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5. Figure 4 Dynamic Changes in Replication Regulation during Development
(A) RT changes during development defining distinct classes of RDs: constitutive domains (replicating always either early or late) and developmentally regulated domains that switch between early and late replication.
(B) Developmentally regulated domains are distinct from constitutive RDs.
Molecular Cell  , DOI: ( /j.molcel )
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