Key Points
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Initiator proteins direct the assembly of DNA synthesis enzymes at chromosomal sites in a highly regulated manner. In bacteria, the initiator DnaA cooperatively oligomerizes at the site of replication fork formation to direct melting of DNA duplex strands and loading of the replicative helicase DnaB. DnaA belongs to the AAA+ superfamily of ATPases, and the binding and hydrolysis of nucleotides have a crucial role in controlling DnaA activity.
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The involvement of DnaA at multiple stages of replication initiation is facilitated by its highly modular domain architecture. Interactions with DnaB are mediated by the extreme N-terminal region, whereas a helix–turn–helix motif located in the C-terminal domain confers the sequence-specific DNA-binding activity needed to recognize the origin of replication. The central region of the protein comprises the highly conserved AAA+ fold and primary oligomerization site.
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Recent structural studies have helped to reveal how ATP facilitates DnaA auto-assembly. Oligomerized DnaA forms a right-handed helical filament that is stabilized through the formation of a bipartite nucleotide-binding pocket between two successive AAA+ domains. The structural features that allow for DnaA filament formation seem to be conserved among cellular initiators from archaea and eukaryotes.
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Bacteria use many regulatory strategies that are dedicated to controlling the initiation of DNA replication. Among these, origin sequestration, DnaA titration, dnaA autoregulation and DnaA inactivation closely monitor events that occur at the bacterial replication origin to optimize the intracellular levels and activity of DnaA.
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The involvement of DNA architectural factors at oriC highlight the cellular context in which initiation takes place. DNA-bending proteins such as Fis (factor for inversion stimulation) and IHF (integration host factor) appear to regulate and fine tune the assembly of DnaA at the replication origin during the cell cycle.
Abstract
In all organisms, multi-subunit replicases are responsible for the accurate duplication of genetic material during cellular division. Initiator proteins control the onset of DNA replication and direct the assembly of replisomal components through a series of precisely timed protein–DNA and protein–protein interactions. Recent structural studies of the bacterial protein DnaA have helped to clarify the molecular mechanisms underlying initiator function, and suggest that key structural features of cellular initiators are universally conserved. Moreover, it appears that bacteria use a diverse range of regulatory strategies dedicated to tightly controlling replication initiation; in many cases, these mechanisms are intricately connected to the activities of DnaA at the origin of replication. This Review presents an overview of both the mechanism and regulation of bacterial DNA replication initiation, with emphasis on the features that are similar in eukaryotic and archaeal systems.
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Acknowledgements
M.L.M. acknowledges support from the National Science Foundation predoctoral fellows programme. Support for this work was provided to J.M.B. by the National Institutes of Health (GM071747).
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DATABASES
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FURTHER INFORMATION
Glossary
- Negatively supercoiled DNA
-
Supercoiled DNA with a negative average linking difference; DNA that is underwound with respect to a relaxed duplex.
- Replisome
-
A multi-protein complex assembled at oriC that contains all the enzymes required for DNA replication.
- Dimethylsulphate (DMS) footprinting
-
An assay that identifies a region of DNA that is involved in DNA–protein interactions. DMS methylates guanine nucleotides at the N7 position in the major groove. Protein binding protects this site from methylation, creating a characteristic pattern or footprint.
- AAA+ ATPases
-
A superfamily of proteins with one or two nucleotide-binding domains (AAA modules), which often form ring-like oligomers and function as molecular remodelling factors for diverse cellular processes.
- Positive DNA supercoils
-
Supercoiled DNA with a positive average linking difference; DNA that is overwound with respect to a relaxed duplex.
- Negative writhe
-
Writhe is the geometric parameter used to describe the axial paths of a DNA superhelix (two DNA duplexes) as they wrap around each other in space. To maintain a constant helical pitch (or twist), negatively supercoiled DNA often adopts a negative writhe.
- Positive torodial wrap
-
Some proteins can spatially bend or wrap DNA around their surface. A toroidal wrap refers to the bending of a DNA duplex into a near-circle, much like the spiral coiling of a telephone cord. A positive wrap indicates that the coils have a right-handed pitch.
- DNA sliding clamp
-
A doughnut-shaped protein complex that threads the DNA through its hole while tethering the polymerase to DNA.
- Cracked-ring particles
-
The vast majority of AAA+ proteins form ring-shaped hexamers. A few (such as the processivity clamp loaders) do not seal completely, leaving a notch or crack in the ring.
- Dam methyltransferase
-
An N6-adenine methyltransferase found in bacteria.
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Mott, M., Berger, J. DNA replication initiation: mechanisms and regulation in bacteria. Nat Rev Microbiol 5, 343–354 (2007). https://doi.org/10.1038/nrmicro1640
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DOI: https://doi.org/10.1038/nrmicro1640
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