Eukaryotic Replication Origins and Initiation of DNA Replication

Abstract

Eukaryotic deoxyribonucleic acid (DNA) replication begins at specific genomic sites called replication origins that serve as assembly sites for prereplication complexes (preRCs). PreRCs include proteins that recognise origin sequences, helicases that separate the two strands of DNA and accessory proteins that facilitate helicase binding and interaction with cell cycle regulatory pathways. Assembly of preRCs is required for initiation of DNA replication which occurs after those complexes recruit additional proteins including DNA polymerases. The sequence requirements for replication origins vary but they all include several distinct DNA elements that act synergistically to facilitate preRC assembly. The number of potential replication origins is higher than the number of actual replication initiation sites. Epigenetic processes and metabolic conditions dynamically select the location of replication initiation events of each cell cycle to insure complete and accurate replication of the entire genome in coordination with gene expression and chromatin condensation.

Key Concepts:

  • Replication initiates at distinct chromosomal locations that recruit prereplication (preRC) complexes.

  • PreRCs are recruited sequentially, each step subject to strict regulation to prevent rereplication.

  • Cyclin‐dependent kinases (CDK) levels change during the cell cycle. Low CDK activity is required for preRC assembly as cells exit mitosis. High CDK activity is required for activation of existing preRCs and initiation of DNA synthesis, while simultaneously suppressing assembly of new preRCs.

  • Replication origin sequences vary among metazoans, but the functions of proteins that bind replication origins are conserved.

  • Eukaryotic origins exhibit a modular structure. Modularity is detectable in single‐cell eukaryotes such as yeast and is more pronounced in metazoans, in which replication origins often cluster.

  • Not all potential replication origins are activated in each cell cycle. Utilisation of replication origins is regulated dynamically to facilitate coordination with other metabolic processes occurring on chromatin.

  • Either hyperactivation or suppression of replication origins can damage DNA and cause chromosomal rearrangements, suggesting that spacing replication initiation events at defined intervals facilitates genomic stability.

Keywords: ARS; DNA synthesis; origin recognition proteins; ORC; cell division cycle proteins; Mcm proteins; DNA unwinding; prereplication complex; preinitiation complex; replicator

Figure 1.

Basic organisation of replication origins. Red indicates sequence elements that are required under all conditions (core components), whereas yellow indicates sequence elements (transcription factor‐binding sites) that facilitate replication under some conditions (auxiliary components). Arrows indicate protein:protein interactions. Origins contain an A:T‐rich element (A/T) with adenines on one strand and thymines on the other, an origin recognition element (ORE) and a DNA‐unwinding element (DUE).

Figure 2.

Assembly and activation of prereplication complexes. Reproduced from Aladjem , with permission from Nature Publishing Group.

Figure 3.

Molecular interaction map of the initiation of DNA replication. An interactive version of the map can be found at http://discover.nci.nih.gov/mim. Annotations for the Molecular Interaction Map (an interactive version can be found online: http://discover.nci.nih.gov/mim/).

Figure 4.

Replication origins that function in eukaryotic cells. The Simian virus 40 (SV40) core origin (64 bp) consists of an origin recognition element (ORE) that is required for T‐antigen binding, an easily unwound sequence (DNA‐unwinding element, DUE) where DNA unwinding begins and an A:T‐rich element containing adenines on one strand and thymines on the other. Together these components occupy ∼160 bp of DNA and exhibit autonomously replicating sequence (ARS) activity. Auxiliary elements bind a T‐antigen dimer (aux‐1) and transcription factor Sp1 (aux‐2). The spacing and orientation of these elements are critical and therefore represent a rigid modular anatomy. Replication origins in the budding yeast Saccharomyces cerevisiae consist of 100–150 bp that exhibit ARS activity. Origins consist of two core elements (A and B1) that occupy ∼43 bp and constitute the binding site for the six‐protein origin recognition complex (ORC), and a DUE that generally contains a genetically defined B2 element. Some origins also contain an auxiliary element (B3) that binds transcription factor Abf‐1. Each element is interchangeable with homologous elements from other S. cerevisiae origins and therefore exhibits a flexible modular anatomy. Yeast origins are context sensitive. Replication origins in the fission yeast S. pombe consist of at least one ARS element that is 0.5–1 kb in size. In some cases, multiple ARS elements in close proximity form an initiation zone in which replication bubbles appear to occur randomly, but in fact, originate from specific ARS elements. Whether or not S. pombe origins exhibit a modular anatomy is not yet known. In mammalian cells, some origins consist of a large intergenic initiation zone (shaded region) defined by two‐dimensional gel origin‐mapping methods and one or more high‐frequency initiation sites (OBRs) defined by nascent strand origin‐mapping methods (e.g. the dhfr and rrna gene regions). Other origins such as the Lamin B2 gene region consist of a single OBR that exhibits a cell cycle‐dependent DNA footprint (ORC?) reminiscent of those at S. cerevisiae origins. The Lamin B2 origin also overlaps three transcription factor‐binding sites belonging to the promoter of a downstream gene. Initiation events in the intergenic region (0.6 kb) downstream of the Lamin B gene have not been analysed by two‐dimensional gel analysis.

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Further Reading

Antequera F (2004) Genomic specification and epigenetic regulation of eukaryotic DNA replication origins. The EMBO Journal 23: 4365–4370.

Blow JJ and Gillespie PJ (2008) Replication licensing and cancer – a fatal entanglement? Nature Reviews. Cancer 8: 799–806.

Donaldson AD (2005) Shaping time: chromatin structure and the DNA replication programme. Trends in Genetics 21: 444–449.

Machida YJ, Hamlin JL and Dutta A (2005) Right place, right time, and only once: replication initiation in metazoans. Cell 123: 13–24.

Sclafani RA and Holzen TM (2007) Cell cycle regulation of DNA replication. Annual Review of Genetics 41: 237–280.

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DePamphilis, Melvin L, and Aladjem, Mirit I(Sep 2010) Eukaryotic Replication Origins and Initiation of DNA Replication. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001055.pub2]