Where and when to start: Regulating DNA replication origin activity in eukaryotic genomes

Abstract

In eukaryotic genomes, hundreds to thousands of potential start sites of DNA replication named origins are dispersed across each of the linear chromosomes. During S-phase, only a subset of origins is selected in a stochastic manner to assemble bidirectional replication forks and initiate DNA synthesis. Despite substantial progress in our understanding of this complex process, a comprehensive 'identity code' that defines origins based on specific nucleotide sequences, DNA structural features, the local chromatin environment, or 3D genome architecture is still missing. In this article, we review the genetic and epigenetic features of replication origins in yeast and metazoan chromosomes and highlight recent insights into how this flexibility in origin usage contributes to nuclear organization, cell growth, differentiation, and genome stability.

Keywords: 3D Genome Organization; DNA replication; chromatin structure; histone modifications; origin clustering; origins of replication; replication timing.

Figure 1.

DNA sequence specificity of yeast and mammalian replication origin. (a) Illustration of sequence elements of E. coli replication origin (oriC). The DUE is flanked on one side by multiple high- and weak-affinity DnaA-boxes. Specific replication origin sequence elements for S. cerevisiae (b), S. pombe (c), and metazoan cells (d) are shown. DUE – DNA unwinding element, IHF – integration host factor, G4 – G quadruplex, OGRE – origin G-rich repeated element.

Figure 2.

Nucleosome positioning and histone modifications at replication origins. Various histone marks associated with early and late replication origins in yeast (a) and mammalian cells (b) are shown. Histone acetylation at nucleosomes adjacent to origin generally creates open chromatin structure and is a feature of early replication origins in both yeast and metazoans. Euchromatic regions increase the probability of association with limiting replication factors like CDC45. Hypoacetylation creates compact chromatin structure and limit binding of replication factors. Various writers and erasers are illustrated on top of specific histone modifications. HDACs – histone deacetylases, HATs – histone acetylases, HMTs – histone methyltransferases, HDMs – histone demethylases.

Figure 3.

Nuclear organization of replication origins. Genome organization of replication domains in (a) mammalian and (b) yeast. In both models, early replicating domains are clustered in the center region while late replicating domains are at peripheral region. (a) In metazoans, early replication domains are gene-rich, GC-rich, and enriched with regulatory elements like promoters and enhancers, the TAD boundary is insulated by CTCF. Late replicating domains are AT-rich and gene-poor. (b) In yeast, early replicating domains are mediated mainly by Fkh1/2, the late replicating domains are located at telomeric regions and mediated by Rif1.