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Review
. 2019 Sep 12;15(9):e1008320.
doi: 10.1371/journal.pgen.1008320. eCollection 2019 Sep.

Origins of DNA Replication

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Free PMC article
Review

Origins of DNA Replication

Babatunde Ekundayo et al. PLoS Genet. .
Free PMC article

Erratum in

  • Correction: Origins of DNA replication.
    PLOS Genetics Staff. PLOS Genetics Staff. PLoS Genet. 2019 Dec 19;15(12):e1008556. doi: 10.1371/journal.pgen.1008556. eCollection 2019 Dec. PLoS Genet. 2019. PMID: 31856160 Free PMC article.

Abstract

In all kingdoms of life, DNA is used to encode hereditary information. Propagation of the genetic material between generations requires timely and accurate duplication of DNA by semiconservative replication prior to cell division to ensure each daughter cell receives the full complement of chromosomes. DNA synthesis of daughter strands starts at discrete sites, termed replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, organisms have evolved surprisingly divergent strategies that control replication onset. Here, we discuss commonalities and differences in replication origin organization and recognition in the three domains of life.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1
Models for bacterial (A) and eukaryotic (B) DNA replication initiation. A) Circular bacterial chromosomes contain a cis-acting element, the replicator, that is located at or near replication origins. i) The replicator recruits initiator proteins in a DNA sequence-specific manner, which results in melting of the DNA helix and loading of the replicative helicase onto each of the single DNA strands (ii). iii) Assembled replisomes bidirectionally replicate DNA to yield two copies of the bacterial chromosome. B) Linear eukaryotic chromosomes contain many replication origins. Initiator binding (i) facilitates replicative helicase loading (ii) onto duplex DNA to license origins. iii) A subset of loaded helicases is activated for replisome assembly. Replication proceeds bidirectionally from origins and terminates when replication forks from adjacent active origins meet (iv).
Fig 2
Fig 2. Origin organization and recognition in bacteria.
A) Schematic of the architecture of E. coli origin oriC, Thermotoga maritima oriC, and the bipartite origin in Helicobacter pylori. The DUE is flanked on one side by several high- and weak-affinity DnaA-boxes as indicated for E. coli oriC. B) Domain organization of the E. coli initiator DnaA. The magenta circle indicates the single-strand DNA binding site. C) Models for origin recognition and melting by DnaA. In the two-state model (left panel), the DnaA protomers transition from a dsDNA binding mode (mediated by the HTH-domains recognizing DnaA-boxes) to an ssDNA binding mode (mediated by the AAA+ domains). In the loop-back model, the DNA is sharply bent backwards onto the DnaA filament (facilitated by the regulatory protein IHF [40]) so that a single protomer binds both duplex and single-stranded regions. In either instance, the DnaA filament melts the DNA duplex and stabilizes the initiation bubble prior to loading of the replicative helicase (DnaB in E. coli). HTH–helix-turn-helix domain, DUE–DNA unwinding element, IHF–integration host factor.
Fig 3
Fig 3. Origin organization and recognition in archaea.
A) The circular chromosome of Sulfolobus solfataricus contains three different origins. B) Arrangement of initiator binding sites at two S. solfataricus origins, oriC1 and oriC2. Orc1-1 association with ORB elements is shown for oriC1. Recognition elements for additional Orc1/Cdc6 paralogs are also indicated, while WhiP binding sites have been omitted. C) Domain architecture of archaeal Orc1/Cdc6 paralogs. The orientation of ORB elements at origins leads to directional binding of Orc1/Cdc6 and MCM loading in between opposing ORBs (in B). (m)ORB–(mini-)origin recognition box, DUE–DNA unwinding element, WH–winged-helix domain.
Fig 4
Fig 4. Origin organization and recognition in eukaryotes.
Specific DNA elements and epigenetic features involved in ORC recruitment and origin function are summarized for S. cerevisiae, S. pombe, and metazoan origins. A schematic of the ORC architecture is also shown, highlighting the arrangement of the AAA+ and winged-helix domains into a pentameric ring that encircles origin DNA. Ancillary domains of several ORC subunits involved in targeting ORC to chromosomes are included. Other regions in ORC subunits may also be involved in initiator recruitment, either by directly or indirectly associating with partner proteins. A few examples are listed. Note that the BAH domain in S. cerevisiae Orc1 binds nucleosomes [105] but does not recognize H4K20me2 [106]. BAH–bromo-adjacent homology domain, WH–winged-helix domain, TFIIB–transcription factor II B-like domain in Orc6, G4 –G quadruplex, OGRE–origin G-rich repeated element.

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Cited by 1 article

  • Correction: Origins of DNA replication.
    PLOS Genetics Staff. PLOS Genetics Staff. PLoS Genet. 2019 Dec 19;15(12):e1008556. doi: 10.1371/journal.pgen.1008556. eCollection 2019 Dec. PLoS Genet. 2019. PMID: 31856160 Free PMC article.

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Publication types

Grant support

This work was supported by the Novartis Research Foundation and the European Research Council under the European Union’s Horizon 2020 research and innovation program (ERC-STG-757909). The funders had no role in the preparation of the article.
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