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Review
. 2017:1042:43-59.
doi: 10.1007/978-981-10-6955-0_2.

Regulation of Replication Origins

Anna B Marks  1 , Haiqing Fu  1 , Mirit I Aladjem  2
Affiliations
Review

Regulation of Replication Origins

Anna B Marks et al. Adv Exp Med Biol. 2017.

Abstract

In eukaryotes, genome duplication starts concomitantly at many replication initiation sites termed replication origins. The replication initiation program is spatially and temporally coordinated to ensure accurate, efficient DNA synthesis that duplicates the entire genome while maintaining other chromatin-dependent functions. Unlike in prokaryotes, not all potential replication origins in eukaryotes are needed for complete genome duplication during each cell cycle. Instead, eukaryotic cells vary the use of initiation sites so that only a fraction of potential replication origins initiate replication each cell cycle. Flexibility in origin choice allows each eukaryotic cell type to utilize different initiation sites, corresponding to unique nuclear DNA packaging patterns. These patterns coordinate replication with gene expression and chromatin condensation. Budding yeast replication origins share a consensus sequence that marks potential initiation sites. Metazoan origins, on the other hand, lack a consensus sequence. Rather, they are associated with a collection of structural features, chromatin packaging features, histone modifications, transcription, and DNA-DNA/DNA-protein interactions. These features confer cell type-specific replication and expression and play an essential role in maintaining genomic stability.

Keywords: Cell cycle regulation; Chromatin organization; DNA replication; Histone modification; Replication origin licensing; Replication timing.

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Figures

Fig. 1
Fig. 1
Pre-replication complex proteins bind in a stepwise manner throughout G1. Recruited during the M to G1 transition, the origin recognition complex (ORC) is a platform to recruit a conserved group of helicases, polymerases, and accessory proteins that catalyze the initiation of DNA replication. ORC binds to chromatin as cells emerge from mitosis. Licensing factors Cdc6 and Cdt1 bind to ORC, followed by the inactive form of the replicative helicase MCM2-7. Additional proteins are required to activate the MCM helicase and initiate DNA replication. Specifically, the inactive MCM2-7 helicase then interacts with CDC45, MCM10, and GINS (Sld5, Psf1, Psf2, Psf3) to form the complete helicase (CMG) complex. Cyclin-dependent kinase (CDK)- and Dbf4-dependent kinase (DDK)-mediated phosphorylation activates proteins and allows Cdc45 interacts with Treslin (Sld3 in yeast). Sld2/RecQL4 and DPB11/TopBP1 are then recruited to the complex. Chromatin-associated DNA polymerases (Pol-α and pol-δ), replication protein A (RPA), CMG, and Dpb11/TopBP1 then initiate DNA replication
Fig. 2
Fig. 2
While the profiles of activated replication origins are similar within cell line, specific replication origin chosen by cells within that population varies in location and replication time. Most origins exhibit flexible initiation patterns, where the specific origins activated differ between cells. When such flexible origins remain “dormant” and do not initiate replication, they replicate passively from adjacent replication forks
Fig. 3
Fig. 3
(a) Metazoan replication origins share several sequence features. Origins generally associate with regions that exhibit strand asymmetry, CpG islands, G-quadruplexes, transcription start sites, origin G-rich-repeated elements (OGREs), and regions of DNase hypersensitivity. In agreement, local histone modifications correlate with and can determine replication origin locations and timing. Early replicating regions associate with H3K4me1/2/3, H3K9ac, H3K18ac, H3K36me3, and H3K27ac. These histone modifications also associate with open chromatin and are enriched in moderately active transcription start sites. Late replicating regions tend to associate with H3 and H4 hypoacetylation, H3K9 and H3K27 methylation, and are found in heterochromatic regions. (b) Distal DNA sequences affect origin activity and transcriptional through long-distance interactions. Such interactions can be mediated via protein interaction with enhancers and locus control regions, by chromatin remodeling factors and transcriptional activators that bind enhancers and locus control regions, and by long noncoding RNAs
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