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Review
. 2018 Jun:52:43-50.
doi: 10.1016/j.ceb.2018.01.004. Epub 2018 Feb 4.

Replication timing and nuclear structure

Haiqing Fu  1 , Adrian Baris  1 , Mirit I Aladjem  2
Affiliations
Review

Replication timing and nuclear structure

Haiqing Fu et al. Curr Opin Cell Biol. 2018 Jun.

Abstract

DNA replication proceeds along spatially and temporally coordinated patterns within the nucleus, thus protecting the genome during the synthesis of new genetic material. While we have been able to visualize replication patterns on DNA fibers for 50 years, recent developments and discoveries have provided a greater insight into how DNA replication is controlled. In this review, we highlight many of these discoveries. Of great interest are the physiological role of the replication timing program, cis and trans-acting factors that modulate replication timing and the effects of chromatin structure on the replication timing program. We also discuss future directions in the study of replication timing.

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Figures

Figure 1
Figure 1
Replication timing and nuclear structure: To co-ordinate DNA replication with transcription and chromatin assembly, chromatin inside the nucleus is organized into distinct replication timing domains. Replication timing domains are highly colocalized with topologically associating domains (TADs). Some domains contain euchromatin with actively transcribed genes and usually replicate at early S phase; some domains contain heterochromatin with silenced genes and replicate at late S phase. Inside each replication timing domain, many origins cluster together and initiate at similar times. Replication timing can be quantified by measuring relative copy number in proliferating cells. Replication timing domains can be detected as magabase-sized peaks when relative copy number is plotted, and replication origins can be detected as small peaks (ripples) within replication timing domains. Eu: euchromatin. Het: heterchromatin. Ori: origins. NE: nuclear envelope.
Figure 2
Figure 2
Cis- and trans-factors establish early DNA replication domains with open chromatin and late DNA replication domains with heterochromatin. In addition to replicators and replication initiation complexes, other cis- and trans-factors affect nuclear structures and DNA replication timing. For example, RepID regulates DNA replication initiation by forming loops linking enhancer and/or locus control regions with replication origins; Fkh1/2 cluster groups of origins in the G1 phase for early replication in S phase; Rif1 and ORCA prevent late replicating regions from replicating earlier. Long non-coding RNAs can also affect chromatin structure and replication timing locally and mediate the action of distal regulators.
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