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Initiation of DNA replication: lessons from viral initiator proteins

Nature Reviews Molecular Cell Biology volume 4, pages 777–785 (2003)Cite this article

Key Points

  • Initiator proteins recognize and bind to the replicator and serve to initiate DNA replication. The activities that are provided by initiator proteins range from recognition of the ori and recruitment of replication factors, to melting of double-stranded DNA and replicative DNA-helicase activity.

  • A surprising feature of initiator proteins is that they bind DNA with modest sequence specificity, although marking of the site of initiation is a task that is likely to require high specificity. For viral initiator proteins, the low specificity is caused by the presence of a nonspecific DNA-binding activity that is required for the melting and unwinding steps. Highly specific binding for ori recognition is generated by inhibition of the nonspecific binding activity.

  • DNA-binding domains, which direct site-specific DNA binding of initiator proteins, are structurally related in initiators from different virus groups and demonstrate a common ancestry of these domains with proteins that bind RNA.

  • Viral initiator proteins, using multiple protein–DNA and protein–protein interactions, assemble in an ordered fashion into different complexes that, in succession, provide sequence-specific recognition, DNA-melting activity and DNA-helicase activity. This 'hardwiring' of the successive initiator activities ensures a highly efficient and robust initiation process.

  • We suggest that one way to understand the complex cellular initiator proteins is to understand in some detail how viral initiators function: such an understanding will assist in the identification and characterization of the corresponding functions that are present in the cellular initiators.

Abstract

Initiator proteins are key components of the DNA replication machinery that determine where initiation will occur. In the past few years, due to a greatly improved understanding of what viral initiators look like and how they function, we can now identify the basic tasks that are required of initiators, as well as begin to comprehend what activities are required to perform these tasks. The improved knowledge of the viral initiators also demonstrates an unexpected level of conservation between different viral initiators, which might extend also to their cellular counterparts.

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Figure 1: Initiation of DNA replication.
Figure 2: ATP-dependent loading of E1.
Figure 3: E2 generates specificity by inhibiting nonspecific DNA binding.
Figure 4: The DNA-binding domains of viral initiator proteins are structurally related to RNA-binding proteins.
Figure 5: Assembly of viral initiator complexes requires multiple interactions.
Figure 6: Functional model for the double hexamer as a bi-directional helicase machine.
Figure 7: The double-hexamer helicase machine.

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Acknowledgements

We thank Xiaojiang Chen for communicating results before publication. A.S. was supported by CA 13106 from the National Cancer Institute.

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    Arne Stenlund

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DATABASES

GenBank

E1

E2

T-ag

LocusLink

DNA polymerase-α

MCM2

MCM3

MCM4

MCM5

MCM6

MCM7

RPA

Glossary

REPLICATOR

A genetically defined term denoting the DNA sequence to which the initiator binds and that controls the initiation of DNA replication.

ORC

(Origin recognition complex). An evolutionarily conserved six-polypeptide complex, which serves as the initiator in eukaryotes.

DnaA

A single-subunit protein that is the initiator in E. coli. DnaA is also required for the replication of many bacterial plasmids.

HELICASE

An enzyme that catalyses unwinding (that is, strand separation) of double-stranded DNA or RNA.

CLAMP LOADER

The machinery in E. coli and eukaryotes that loads the sliding-clamp-like DNA polymerase processivity factors (β-clamp and PCNA in E. coli and eukaryotes, respectively) onto DNA.

ROLLING-CIRCLE REPLICATION

(RCR). A basic mechanism for replication of DNA that is used by plasmids, phages and single-stranded viruses. RCR is characterized by the generation of a single-stranded nick in the template, exposing a 3′-end, which can be extended by a DNA polymerase, thereby displacing the parental strand. The products are concatemers of unit-length single-stranded DNA.

RPA

(Replication protein A). A three-subunit single-stranded DNA-binding protein in eukaryotes.

SSB

(Single-stranded DNA-binding protein). A bacterial single-stranded DNA-binding protein that has an essential role in replication, recombination and repair.

MCM

(Mini chromosome maintenance). A set of proteins that were originally identified as affecting the maintenance of plasmids in yeast. MCM2–7 are thought to be the replicative DNA helicases of eukaryotic cells.

TOPOISOMERASE

An enzyme that changes DNA supercoiling by inserting or removing superhelical twists.

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Stenlund, A. Initiation of DNA replication: lessons from viral initiator proteins. Nat Rev Mol Cell Biol 4, 777–785 (2003). https://doi.org/10.1038/nrm1226

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