DNA Replication Origins


In all living organisms, genome replication is essential for their development and maintenance. In the genome of simple organisms, such as bacteria and small eukaryotic deoxyribonucleic acid (DNA) viruses, DNA replication starts from a well‐characterised single origin. In complex eukaryotes, such as metazoans, DNA replication starts from dozens of thousands of origins spread along the different chromosomes. This high number of origins, together with the technical problems encountered in finding reliable methods for their large‐scale mapping, made difficult their characterisation. However, owing to the new genome‐wide approaches developed in the past few years, we have now a better understanding of how replication origins are established in higher eukaryotes. These studies have shown an intrinsic correlation between replication origins and other genome features, such as gene transcription and epigenetic regulation, and revealed an amazing flexibility in their usage.

Key Concepts:

  • Replication origins are defined by specific DNA sequences in bacteria, viruses and Saccharomyces cerevisiae, but not in Schizosaccharomyces pombe and metazoans.

  • DNA replication origins are activated in a defined temporal order, called timing of DNA replication.

  • DNA replication origins are flexible: only a subset of them is activated at each cell cycle.

  • DNA replication takes place at specific subnuclear structures, called replication foci.

  • The number and position of replication origins to be activated may vary according to the developmental or growing conditions.

Keywords: DNA replication; chromatin; epigenetic; transcription; development

Figure 1.

Specificity of DNA replication initiation, from bacteria to metazoans. The bacterial chromosome epitomises the prototypic replicon. It contains a single, genetically defined, specific sequence (oriC) to which the replication initiator binds. SV40 is the prototype of a eukaryotic viral DNA replicon. It contains a single, genetically defined specific sequence to which T‐antigen, the viral‐encoded replication initiator, binds. All S. cerevisiae origins, ARS, share an 11 bp consensus sequence and are genetically defined; however, many ARS elements that are functional in plasmids are not functional in a chromosomal context. Multicellular eukaryotes have mainly site‐specific origins. These sites usually contain one or several potential origins. The ORC complex recognises the sequence‐specific yeast origin. In human and other multicellular eukaryotes, the ORC complex is also involved in origin recognition through a mechanism that may not involve strict consensus sequence specificity.

Figure 2.

DNA replication origin features. Summary of the features are often seen in eukaryotic DNA replication origins. Several characteristics have been described at metazoan replication origins, but they are not present at all origins. Rather, they represent different marks or modules that can contribute to the selection of a given origin. MAR, matrix‐attachment region. Modified with permission from Méchali (). © Nature Publishing Group.

Figure 3.

Spatial organisation of replication origins. (a) Replicons are organised as functional units that contain one or several potential DNA replication origins. Activation of one origin within a replicon silences the others. The choice of origin to be activated within each replicon can be either stochastic or based on the specific requirements of developmental cell fates. Replicon clusters include several consecutive replicons that are activated simultaneously (Berezney et al., ). (b) Representation of replicons as chromatin loops where activation of one origin silences the other origins contained in the same replicon. Replication foci are due to the clustering of several replicons. They can be detected by labelling nuclei with a fluorescent nucleotide for a short period, followed by visualisation of the replication sites by wide‐field microscopy. Modified with permission from Cayrou et al. (). © National Human Genome Research Institute.



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Further Reading

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Yamazaki S, Hayano M and Masai H (2013) Replication timing regulation of eukaryotic replicons: Rif1 as a global regulator of replication timing. Trends in Genetics 8: 449–460.

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Rodríguez‐Martínez, Marta, and Méchali, Marcel(Aug 2014) DNA Replication Origins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006170.pub2]