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. 2012 Nov;3(11-12):678-96.
doi: 10.1177/1947601912474891.

Back to the origin: reconsidering replication, transcription, epigenetics, and cell cycle control

Adam G Evertts  1 , Hilary A Coller
Affiliations

Back to the origin: reconsidering replication, transcription, epigenetics, and cell cycle control

Adam G Evertts et al. Genes Cancer. 2012 Nov.

Abstract

In bacteria, replication is a carefully orchestrated event that unfolds the same way for each bacterium and each cell division. The process of DNA replication in bacteria optimizes cell growth and coordinates high levels of simultaneous replication and transcription. In metazoans, the organization of replication is more enigmatic. The lack of a specific sequence that defines origins of replication has, until recently, severely limited our ability to define the organizing principles of DNA replication. This question is of particular importance as emerging data suggest that replication stress is an important contributor to inherited genetic damage and the genomic instability in tumors. We consider here the replication program in several different organisms including recent genome-wide analyses of replication origins in humans. We review recent studies on the role of cytosine methylation in replication origins, the role of transcriptional looping and gene gating in DNA replication, and the role of chromatin's 3-dimensional structure in DNA replication. We use these new findings to consider several questions surrounding DNA replication in metazoans: How are origins selected? What is the relationship between replication and transcription? How do checkpoints inhibit origin firing? Why are there early and late firing origins? We then discuss whether oncogenes promote cancer through a role in DNA replication and whether errors in DNA replication are important contributors to the genomic alterations and gene fusion events observed in cancer. We conclude with some important areas for future experimentation.

Keywords: checkpoints; epigenetics; origin; replication; replicon; transcription.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Model for the initiation of DNA replication at the lamin B2 origin. The TET2 enzyme converts methylated cytosine to hydroxymethylated cytosine. The hydroxymethylated cytosine is excised by thymine DNA glycosylase. The E-box with unmodified cytosine is recognized by Myc as origin proteins ORC2, Cdc6, and Cdt1 are bound. Myc recruits MLL, which modifies histone H3 on lysine 4 to the trimethyl form. The histone H3K4me3 mark promotes the binding of HBO1 acetylase and facilitates histone H4 hyperacetylation. The resulting hyperacetylation favors nucleosome remodeling that facilitates the loading of MCM proteins.
Figure 2.
Figure 2.
Topological problems and a potential solution associated with DNA replication. (A) Unwinding of the DNA causes positive supercoils to accumulate ahead of the advancing replication machinery (oval). (B) The topological problem associated with nuclear pore–gated transcribed genes. A model for a replication fork approaching a gene that is gated to the nuclear pore complex is shown. (C) An example of bidirectional replication initiation. The DBF4 origin contains 2 initiation zones. Replication starts at the first zone and progresses in the direction of transcription toward the second initiation zone. Replication then initiates from a second origin and proceeds on the opposite strand.
Figure 3.
Figure 3.
Model for the organization of genomic DNA with respect to DNA replication. Replication origins in open chromatin are grouped together into a replication factory early in S phase. Later in S phase, a different set of origins are clustered together to form a replication factory.
Figure 4.
Figure 4.
Two possible models to explain the lack of long gaps between replication origins. (A) The “domino model” postulates that replication begins at replication origins present in open chromatin. As replication progresses, replication origins in closed chromatin become more accessible as the replication fork unwinds the DNA. (B) An alternative model is that one origin within a cluster of potential origins is selected in each cell for firing. This ensures both the flexibility of origin choice and consistent spacing of origins.
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