Abstract

The initiation of chromosomal replication occurs only once during the cell cycle in both prokaryotes and eukaryotes. Initiation of chromosome replication is the first and tightly controlled step of a DNA synthesis. Bacterial chromosome replication is initiated at a single origin, oriC , by the initiator protein DnaA, which specifically interacts with 9-bp nonpalindromic sequences (DnaA boxes) at oriC . In Escherichia coli , a model organism used to study the mechanism of DNA replication and its regulation, the control of initiation relies on a reduction of the availability and/or activity of the two key elements, DnaA and the oriC region. This review summarizes recent research into the regulatory mechanisms of the initiation of chromosomal replication in bacteria, with emphasis on organisms other than E. coli .

Introduction

The events involved in the initiation of chromosomal replication are similar in Eubacteria, eukaryotes, and Archea: replication starts with the binding of specific initiator protein(s) to DNA sites, termed origins, and results in the localized unwinding of the DNA duplex and the establishment of replication forks. In eukaryotes, chromosomes contain multiple start sites for DNA synthesis, and the initiator origin recognition complex (ORC) is a six-subunit heteromultimer that binds to the origin region. In contrast, bacteria replicate their chromosome(s) from a single replication origin ( oriC ), and the initiation of chromosome replication is mediated by a single initiator protein, DnaA, which specifically interacts with 9-bp nonpalindromic sequences (DnaA boxes) at oriC ( Messer et al. , 2002 ; Kaguni et al. , 2006 ). This process has been particularly well characterized in Escherichia coli . Twenty to 30 DnaA monomers interact with 11 binding sites. Three of these sites are high-affinity binding sites; the others [two 9-mer DnaA boxes, three 6-mer DnaA–ATP boxes ( Weigel et al. , 1997 ; Speck & Messer, 2001 ) and three 9-mer I sites ( Leonard & Grimwade, 2005 )] require oligomerization of DnaA. Erzberger (2002 , 2006) proposed a model of DnaA oligomerization at oriC based on the recently resolved crystal structure of the major part of Aquifex aeolicus DnaA (domains III and IV). In this model, DnaA monomers bound to DnaA boxes together with DnaA monomers oligomerize into right-handed filament; a newly created nucleoprotein complex is stabilized by specific protein–ATP interactions of adjacent DnaA monomers. Additional stability may be provided by domain I, which is responsible for self-oligomerization ( Weigel et al. , 1999 ; Felczak et al. , 2005 ). Wrapping of the oriC region around the DnaA filament promotes a local unwinding of an AT-rich region that leads to the formation of the open complex. Because there are flexible links between the respective DnaA domains responsible for oligomerization, ATP binding, and DNA binding, it is easy to imagine how the origins of other bacteria with different numbers and orientations of DnaA boxes adjust to their cognate DnaA proteins ( Zawilak-Pawlik et al. , 2005 ). As a result of DnaA–DnaB and DnaC–ssDNA interactions, the DnaB/DnaC helicase complex is loaded into the unwound origin region ( Konieczny et al. , 2003 ), and then DnaB loads DnaG ( Lu et al. , 1996 ; Tougu & Marians, 1996 ) and DNA polymerase III ( Kim et al. , 1996 ). The overall architecture of the eukaryotic ORC is very similar to that of DnaA oligomers ( Clarey et al. , 2006 ). This and the importance of ATP binding for ORC–origin interaction exemplify the global similarity of these basic processes. By analogy to the DNA-wrapping activity of DnaA, ORC together with Cdc6 prepares origins for helicase loading through mechanisms related to the established pathway of bacteria ( Clarey et al. , 2006 ).

Replication initiation has to occur at the correct time in the cell cycle, and any one origin must initiate once and only once per cell cycle ( Boye et al. , 2000 ; Messer, 2002 ; Kaguni et al. , 2006 ). In Eubacteria, eukaryotes, and, very likely, Archaea as well, replication is controlled at the initiation stage ( Maaloe & Kjeldgaard, 1966 ). Various mechanisms are involved in the regulation of this process. In Eubacteria, the control of initiation relies on a reduction of the availability and/or activity of both the DnaA protein and the oriC region at the various steps after initiation, for example before unwinding and/or immediately after the establishment of replication forks.

Regulatory mechanisms in E. coli – a short overview

The initiation of replication is controlled by affecting the assembly of the orisomes (protein– oriC complexes). Recent extensive studies have shown that the E. coli orisome structure is dynamic, changing in stages as it progresses through the cell cycle of this bacterium ( Cassler et al. , 1995 ; Leonard & Grimwade, 2005 ; Schaeffer et al. , 2005 ). In E. coli , several orisome components have been identified, including the histone-like DNA-binding proteins IHF and Fis, and other oriC -binding elements such as HU, Dpi, IciA, Cnu, Hha, Rob, SeqA, and ArcA ( Kim et al. , 2005 ). Orisome assembly is regulated by a dynamic interplay among these proteins; for example, Fis and IHF directly modulate the interaction of DnaA–ATP with its weaker binding sites, while HU modulates the binding of IHF to oriC and presumably enhances the ability of DnaA to unwind the origin ( Hwang & Kornberg, 1992 ; Ryan et al. , 2004 ). In contrast to IHF, IciA inhibits the unwinding of oriC . However, the contribution of IciA and other proteins, Dpi, Cnu, Hha, and Rob, to orisome assembly or disassembly during the cell cycle remains to be elucidated. The assembly of orisomes could also be affected by proteins that directly interact with DnaA. Recently, DiaA, a novel DnaA-binding protein crucial to ensuring the timely initiation of replication, was identified in E. coli ( Ishida et al. , 2004 ).

Three key negative regulation mechanisms preventing reinitiation from the newly replicated origins have been described in E. coli : (1) inhibition of DnaA activity, (2) titration of the free form of DnaA, and (3) sequestration of the oriC . Inactivation of DnaA protein occurs by conversion of the active initiator DnaA–ATP form to inactive DnaA–ADP, which is stimulated by the replisome elements, namely the DnaN sliding clamp of DNA polymerase III and Hda protein, and is called RIDA (regulatory inactivation of DnaA) ( Katayama et al. , 1998 ; Kato & Katayama, 2001 ; Gon et al. , 2006 ; Riber et al. , 2006 ). A second mechanism preventing reinitiation involves titration of DnaA protein by a cluster of high-affinity DnaA boxes (named datA , D na At itration), which reduces the level of DnaA shortly after this region is duplicated. The datA region is able to bind over 300 DnaA molecules ( Kitagawa et al. , 1998 ). In the third regulatory mechanism, the newly replicated and therefore hemimethylated oriC regions are sequestered by the binding of SeqA protein. SeqA recognizes GATC sequences overrepresented within oriC and prefers binding to hemimethylated over binding to fully or unmethylated oriC .

These three mechanisms of E. coli have been discussed in a number of excellent reviews ( Boye et al. , 2000 ; Katayama et al. , 2001 ; Messer et al. , 2002 ; Margolin & Bernander 2004 ; Camara et al. , 2005 ; Cunningham & Berger, 2005 ; Kato et al. 2005 ; Lobner-Olesen et al. , 2005 ; Kaguni et al. , 2006 ). Because much of what is know about the regulation of the initiation of bacterial chromosomal replication comes from studies of E. coli , this review focuses mainly on regulatory mechanisms in organisms other than E. coli ( Fig. 1 ).

Figure 1

Regulatory mechanisms of the initiation of bacterial chromosome replication.

Figure 1

Regulatory mechanisms of the initiation of bacterial chromosome replication.

Escherichia coli -like mechanisms in other organisms

The inactivation of DnaA–ATP by ATP hydrolysis is likely to take place in all bacteria possessing a dnaA gene. Besides being established for E. coli DnaA, ATPase activity has also been demonstrated for other bacterial DnaA proteins, including Bacillus subtilis ( Fukuoka et al. , 1990 ) , Helicobacter pylori (A. Zawilak-Pawlik unpublished results), Mycobacterium tuberculosis ( Yamamoto et al. , 2002 ; Madiraju et al. , 2006 ), Streptomyces coelicolor ( Majka et al. , 1997 ), Thermus thermophilus ( Schaper et al. , 2000 ), and Thermotoga maritima ( Ozaki et al. , 2006 ). So far, all sequenced dnaA genes encode an AAA+ATPase motif responsible for the binding and hydrolysis of ATP. Furthermore, this motif is also present in proteins that initiate chromosome replication in eukaryotes (three ORC proteins, namely Orc1p, Orc4p and Orc5p, and Cdc6) ( Speck et al. , 2005 ) and Archaea (Cdc6/Orc1) ( Robinson & Bell, 2005 ). All these proteins are replication-active in the ATP-bound form ( Lee and Bell 2000 ; Davey et al. , 2002 ). Thus, ATP binding and hydrolysis acts as a universal switch that regulates the initiation of replication in three domains of life. Little is known about the mechanism(s) responsible for the inactivation of the ATP-bound form of initiators. It should be noted that orthologues of Hda are present only in certain gammaproteobacterial genomes, suggesting the presence of different regulation systems in the replication initiation process of Eubacteria.

Titration of the DnaA protein by a cluster of high-affinity DnaA boxes localized outside oriC also appears to be involved in the regulation of chromosome replication in other bacteria. The S. coelicolor chromosome contains a cluster of high-affinity DnaA boxes in the vicinity of the oriC region ( Smulczyk-Krawczyszyn et al. , 2006 ). Deletion of the cluster caused more frequent chromosome replication and led to earlier colony maturation. In contrast, delivery of high-affinity DnaA boxes caused slow colony growth, presumably because of a reduction in the frequency of replication initiation. In silico analysis of bacterial chromosomes revealed that many of them contain at least two clusters of DnaA boxes in the vicinity of the oriC region ( Mackiewicz et al. , 2004 ). Thus the presence of additional clusters of DnaA boxes in chromosomes other than those of E. coli or S. coelicolor suggests that such control may be a common mechanism for many bacteria.

Up until now, sequestration of the oriC region has seemed to be a mechanism exclusively characteristic of E. coli and other enterobacteria. However, some recent data suggest that the initiation of replication of Agrobacterium tumefaciens ( Kahng & Shapiro, 2001 ), Brucella abortus , Caulobacter crescentus ( Stephens et al. , 1995 ), Rhizobium meliloti , and Rickettsia prowazekii , and probably of other organisms from α-subdivision bacteria, might involve an analogous system; these organisms possess a cell cycle-regulated CcrM DNA methyltransferase that recognizes the GANTC sequence ( Stephens et al. , 1996 ). Interestingly, in some bacteria that do not have the sequestration mechanism, such as B. subtilis and Streptomyces , minichromosomes are unstable, and only low copy numbers occur; in contrast to E. coli , minichromosomes of these organisms compete with chromosomes ( Zakrzewska-Czerwińska & Schrempf, 1992 ; Moriya et al. , 1999 ; Paulsson & Chattoraj, 2006 ; Smulczyk-Krawczyszyn et al. , 2006 ). From studies on these bacteria, it is becoming clear that their chromosomal replication control shares some similarities with that of low-copy-number plasmids, such as miniP1. In both cases, DnaA boxes or plasmid iterons (binding sites for initiator protein) serve as incompatibility elements ( Mukhopadhyay & Chattoraj, 2000 , Ogura et al. , 2001 , Park et al. , 2001 ). Perhaps handcuffing (origin pairing causing steric hindrance) may also apply to B. subtilis and Streptomyces replication control.

As in E. coli , the assembly of orisomes in other bacteria is affected by proteins that interact with oriC and/or DnaA. In C. crescentus , IHF and CtrA (see below) bind the oriC region specifically. Bacillus subtilis lacks genes encoding proteins homologous to E. coli accessory proteins, IHF, Hha, Fis, SeqA, Dam, but several novel proteins modulating orisome assembly have been identified in B. subtilis , including Spo0A, an oriC -binding protein (see below), DnaD and DnaB, which participate in loading the DnaC–DnaI helicase complex (equivalent to E. coli DnaBC) at oriC ( Bruand et al. , 2005 ; Zhang et al. , 2005 , 2006 ; Carneiro et al. , 2006 ), and YabA, interacting with DnaA and DnaN ( Noirot-Gros et al. , 2002 , 2006 ; Hayashi et al. , 2005 ). However, their exact biological function in B. subtilis orisome assembly is not yet fully understood. Recently, in H. pylori a novel, essential architectural component of the orisome, HobA, was found (A. Zawilak-Pawlik unpublished results).

In E. coli , DnaA protein, besides being the initiator, is also a transcription factor regulating the expression of genes that are involved in replication (e.g. mioC , nrd ), including its own gene; binding of the DnaA protein to DnaA boxes located within promoter regions influences gene expression ( Messer & Weigel, 1997 ). The DnaA protein also regulates gene expression in B. subtilis ( Goranov et al. , 2005 ), C. crescentus ( Hottes et al. , 2005 ), and, presumably, in other organisms whose promoter regions contain DnaA-binding motifs.

Free-living bacteria

A global network relevant to regulating replication is likely to be more intricate in organisms that undergo a complex life cycle or in those that have to adapt to highly fluctuating environmental conditions. Under unfavourable conditions, the growth rate should be reduced and/or the bacteria should undergo morphological changes. In these organisms the decision ‘to replicate or not to replicate’ has to be precisely controlled at a number of levels. Bacteria, much like eukaryotic cells, coordinate cell division with DNA replication. Little is known about how the replication machinery coordinates its action with other cellular processes in variable environmental conditions. Adaptation in bacterial cells is often achieved through two-component signal-transduction systems, which consist of a sensor kinase and a response regulator. So far, only a few bacterial two-component signal-transduction systems involved in the regulation of replication initiation have been described. One of them is E. coli Arc (anoxic redox control), a two-component signal-transduction system that participates in regulating chromosomal initiation under anaerobic growth conditions ( Iuchi & Weiner, 1996 ). The Arc system regulates the expression of numerous operons in response to respiratory growth conditions. It consists of the ArcB, a transmembrane sensor kinase, and its cognate response regulator, ArcA. Anaerobic conditions that induce the Arc two-component signal-transduction system lead to a reduction in the growth rate. Lee (2001) demonstrated in vitro that ArcA∼P specifically binds the left part of the E. coli oriC region and prevents the formation of the open complex. Thus, oxygen depletion stress promotes the conversion of ArcA to ArcA∼P and its binding to oriC , which consequently reduces the frequency of chromosomal initiation to sustain a slow growth rate in adverse environmental conditions. Similarly, PhoB protein, a transcriptional regulator of the PhoB–PhoR two-component system regulating phosphate uptake, affects E. coli chromosome initiation. PhoB∼P, under reduced phosphate availability, activates iciA transcription ( Han et al. , 1999 ). IciA is a negative regulator of oriC unwinding in vitro ; hence PhoB∼P might reduce the initiation frequency during phosphate starvation.

Switching off replication by preventing a new round of replication must also occur at certain stages of the life cycles of bacteria that undergo cellular differentiation, for example the formation of morphologically different cells ( C. crescentus ) and/or the production of endospores or exospores ( B. subtilis or S. coelicolor ). An interesting example of a response regulator of the two-component system involved in the regulation of the cell cycle, including inhibition of chromosome replication, is CtrA (cell-cycle transcription regulator) in C. crescentus ( McAdams & Shapiro, 2003 ; McGrath et al. , 2004 ). This is a free-living bacterium in an aquatic environment that divides asymmetrically, generating two distinct cell types at each cell division: a stalked cell competent for DNA replication and a swarmer cell that is unable to initiate DNA replication until it differentiates into a stalked cell later in the cell cycle ( Crosson et al. , 2004 ; Brazhnik & Tyson, 2006 ; Holtzendorff et al. , 2006 ; Jensen et al. , 2006 ). In swarmer cells, CtrA∼P binds specifically to five sites located within the oriC region, preventing the formation of the replisome ( Quon et al. , 1998 ; Siam & Marczynski, 2000 ; Wortinger et al. , 2000 ; Marczynski & Shapiro, 2002 ). At the swarmer-to-stalked cell transition, CtrA is temporally degraded by the ClpXP protease, which releases the origin for replication initiation ( Jenal & Fuchs, 1998 ). Shortly after replication initiation, the proteolysis of CtrA is stopped and a positive transcriptional feedback loop results in the accumulation of new CtrA protein ( Domain et al. , 1999 ; Hung & Shapiro, 2002 ), thus preventing premature reinitiation of DNA replication ( Quon et al. , 1998 ). In C. crescentus , DnaA protein is also selectively targeted for proteolysis, but DnaA proteolysis uses a different mechanism from that of CtrA ( Gorbatyuk & Marczynski, 2005 ). Unlike the case for E. coli DnaA, the degradation of C. crescenus DnaA depends on cell-cycle- and nutrition-specific signalling; it takes place preferentially in swarmer cells. In C. crescentus , both proteins, DnaA and CtrA, regulate the transcriptions of multiple genes: DnaA controls the expression of genes encoding several replisome components, and CtrA controls the expression of many genes involved in flagella biogenesis and cell division. In addition to CtrA, a second master regulatory protein, GcrA, is involved in the cell-cycle regulation of C. crescentus ( Holtzendorff et al. , 2006 ). GcrA is present predominantly in stalked cells. GcrA also affects the expression of many genes: it inhibits dnaA expression and activates genes encoding components of the segregation machinery and the ctrA gene (p1 promoter) ( Holtzendorff et al. , 2004 ). Its expression is inhibited by CtrA and activated by DnaA protein ( Collier et al. , 2006 ).

At certain stages of life, usually in response to nutritional stress, bacteria can form dormant, nonreproductive bodies (e.g. spores). The formation of such temporarily inactive cells has to be preceded by the completion of a final replication round and by the prevention of a new round of replication at the initiation step. During sporulation of B. subtilis , a single cell divides asymmetrically (in contrast to vegetative growth) near one pole, producing a small endospore and a large mother cell that participates in the maturation of the spore and finally lyses to release it. In B. subtilis , Spo0A is a key transcriptional regulator controlling the entrance into sporulation. Spo0A belongs to a superfamily of phosphorylation-activated signal-transduction proteins that mediate adaptive responses to environmental or metabolic signals ( Baldus et al. , 1994 ; Burkholder et al. , 2001 ) and activate the transcription of crucial genes for the sporulation process. It has recently been demonstrated that Spo0A is involved in the regulation of replication frequency. In addition to being required for the onset of sporulation, Spo0A is a transcriptional activator/repressor that influences the expression of over 500 genes. Spo0A binds to so-called ‘0A-boxes’, which have been found not only within the promoter regions, but also within the B. subtilis oriC region, suggesting a novel function for the protein. Indeed, Castilla-Liorente (2006) showed that binding of Spo0A protein to ‘0A-boxes’, which overlap with functional DnaA-binding sites of the oriC region, prevents open complex formation.

Recent advances in bacterial cell biology have revealed that the nucleoid is a highly organized structure that undergoes dynamic changes through the cell cycle, for example during segregation ( Errington et al. , 2005 ). Chromosomal regions are organized into highly ordered structures that are placed in discrete spatial locations at specific times. It has been suggested that, in B. subtilis , Soj and Spo0J proteins (ParA and ParB homologues) required for chromosome segregation may be the negative regulator of replication initiation. In vivo , Spo0J binds to eight parS sites distributed around oriC ( Lee et al. , 2003 ; Murray et al. , 2006 ). The formation of a massive nucleoprotein complex that compacts the oriC region presumably prevents reinitiation from the newly replicated origins by reducing origin accessibility for the initiator protein DnaA ( Lee & Grossman, 2006 ). Indeed, deletion of soj and spo0J causes overinitiation of replication in B. subtilis ( Lee & Grossman, 2006 ).

Similarly, in Streptomyces , ParB, besides being the protein involved in segregation, may also regulate the initiation of replication. Streptomyces , which are known for their ability to produce many valuable antibiotics, are among the most striking examples of multicellular bacteria. Their hyphae grow by tip extension, forming a branched vegetative mycelium that consists of hyphal compartments containing multiple chromosomes; thus cross-wall formation is uncoupled from chromosome replication and segregation. During further growth, Streptomyces colonies form an aerial mycelium that develops into long chains of uninucleoidal exospores. At this stage, intensive replication in rapidly growing compartments is subsequently switched off as the chromosomes become condensed and segregated into spores. As in B. subtilis , it was shown that ParB is engaged, particularly during sporulation, in the formation of large nucleoprotein complexes encompassing oriC regions (twenty parS sequences are clustered around the origin) ( Jakimowicz et al. , 2002 , 2005 ). It has been postulated that compaction of the oriC region by ParB may prevent further rounds of replication.

Intracellular pathogens and endosymbionts

Little is known about the signalling pathways that link the facultative intracellular cell cycle of pathogens with the host environment. It has recently been shown that in M. tuberculosis the initiation of chromosome replication is regulated by the signal-transduction system MtrA–MtrB, which is activated by specific host–pathogen interactions. The M. tuberculosis MtrA response regulator affects chromosome replication in a phosphorylation-dependent manner by inducing M. tuberculosis dnaA expression. The dnaA promoter is a MtrA target, as confirmed by immunoprecipitation experiments using anti-MtrA antibodies ( Fol et al. , 2006 ). Elevating the intracellular levels of MtrA has no effect on bacterial growth in broth, while it prevents the proliferation of M. tuberculosis in macrophages and in mice lungs and spleens. In human macrophage cell lines, the transcript levels of dnaA were significantly increased ( c . 40-fold) in an mtrA overexpression strain relative to the wild type. Furthermore, the same phenotypes were observed when dnaA expression was artificially induced ( dnaA was under the control of an inducible promoter), which suggests that the overexpression of DnaA inhibits the proliferation of M. tuberculosis ( Hoskisson & Hutchings, 2006 ). Fol (2006) proposed that the proliferation of M. tuberculosis in vivo depends, in part, on the optimal ratio of phosphorylated to nonphosphorylated MtrA response regulator.

Obligatory intracellular parasites and endosymbionts existing continuously within the host or extremophiles living under extreme conditions (e.g. high temperature) do not experience the extreme environmental fluctuations encountered by free-living bacteria ( Moran et al. , 2002 ). Sequence analysis of their chromosomes has demonstrated that they have lost many genes and regulatory elements, including those involved in the regulation of replication initiation in free-living organisms.

In contrast to the case for pathogens, the proliferation of obligatory endosymbionts has to be beneficial for the host. Thus these organisms needed to adapt their replication in a balanced way so that their growth rates were coordinated with the development of their hosts. The development of a stable symbiosis with cytosolic bacteria might have required a more direct control of DNA replication of the symbionts by the host ( Gil et al. , 2003 ). In extreme cases, some obligatory insect endosymbionts, for example Wigglesworthia glossinidia (endosymbiont of the tsetse fly) ( Akman et al. , 2002 ), Blochmannia floridanus (carpenter ant) ( Gil et al. , 2003 ), Blochmannia pennsylvanicus (black carpenter ant) ( Degnan et al. , 2005 ), and Baumannia cicadellinicola (glassy-winged sharpshooter) ( Wu et al. , 2006 ), lost the dnaA gene ( Foster et al. , 2005 ). The lack of DnaA protein might allow the host to protect itself from overreplication of the bacterium in its cytosol ( Akman et al. , 2002 ). It cannot be excluded that other alternative replication initiation pathways based on priA , priC or recA genes ( Gil et al. , 2003 ; Wu et al. , 2006 ) – commonly used in E. coli to re-establish replication at damage sites – might be used in these endosymbionts. Although Blochmannia also lacks priA, priC and recA genes, it contains recBCD genes, which may play some role in the initiation of replication ( Wu et al. , 2006 ). Buchnera is an interesting endocellular bacterial symbiont of aphids, which, in contrast to Wiggelsworthia and Blochmannia , retains the dnaA gene to initiate replication (in B. aphidicola , only two DnaA boxes were identified within its putative oriC region; Mackiewicz et al. , 2004 ). However, it should be noted that Buchnera resides in vacuole-like organelles, while Wiggelsworthia and Blochmannia directly contact the host cytoplasm.

Organisms that possess more than one chromosome

Not all bacteria have a single chromosome: some bacteria have multiple chromosomes; for example, Vibrio cholerae possesses two chromosomes, while Burkholderia cepacia has three chromosomes. The control of replication in bacteria with multiple chromosomes is much less well understood than that in organisms with a single chromosome. Among the organisms possessing more than one chromosome, the initiation of replication and the mechanism(s) regulating this process have been studied so far only in V. cholerae . This bacterium, the causative agent of cholera, has two differently sized circular chromosomes, namely chromosome I (chrI) and chromosome II (chrII), of 2.96 and 1.07 Mbp, respectively ( Heidelberg et al. , 2000 ). Vibrio cholerae lives primarily as a free organism in aquatic environments and associates with the host only during short outbreaks. Egan & Waldor (2003) suggested that a bipartite genomic arrangement may provide an evolutionary advantage by facilitating a faster replication time or by allowing chromosome-specific replication control in certain environments. However, so far, none of these hypotheses has been experimentally proven. Although the two chromosomes replicate synchronously, they exhibit distinct replication requirements ( Egan & Waldor, 2003 ; Egan et al. , 2004 , 2005 ; Duigou et al. , 2006 ). The structure of oriCI resembles that of E. coli oriC , whereas oriCII shares some features with certain plasmid replicons. The functional oriCII requires internal 12-bp repeats and two hypothetical genes that flank the origin. One of these genes encodes the protein RctB that specifically binds oriCII . DnaA and RctB independently control replication initiation of the two chromosomes chrI and chrII, respectively. Overproduction of DnaA or RctB protein promoted exclusively overinitiation of chromosome I or chromosome II, respectively. The distinct replication requirements of the two origins may minimize competition between chromosomes, ensuring the maintenance of the divided genome, but, on the other hand, raise the question of how the regulation of replication initiation of two chromosomes is coordinated. Although oriCII has very little sequence similarity to oriCI , it contains a single DnaA box and an overrepresentation of GATC sequences, targets for the Dam methyltransferase. Although DnaA protein does not initiate replication of the chromosome II, its minimum concentration is required for the initiation of chromosome II replication. A similar situation is observed in the case of the replication of certain plasmids, including RK2, where DnaA is known to promote their replication, although they encode their own initiators, such as TrfA ( Duigou et al. , 2006 ). The overrepresentation of methylation motifs in both origins, oriCI and oriCII , of V. cholerae and the presence of seqA and dam genes suggest that these factors may mediate the coordination of replication of two chromosomes in a similar manner to sequestration of the E. coli origin. Additional, so far unknown, elements probably coordinate the activity of both initiators, DnaA and RctB.

Streptomyces and Rhizobium belong to the intriguing group of bacteria whose cells are multinucleoidal at certain stage(s) of the cell cycle. Thus these bacteria do not obey the once-and-only-once doctrine of DNA replication at particular life stages. This characteristic feature raises interesting questions on how the replication of multiple chromosomes within a single cell/compartment is regulated. Very little is known about the synchronization and regulation of chromosome replication in the multinucleoidal compartments of Streptomyces . Recent data show that chromosome replication appears to be asynchronous within a single compartment; only selected chromosomes undergo replication at one time ( Ruban-Osmialowska et al. , 2006 ). Rhizobium endosymbiotic soil bacteria can incite root nodule formation in certain leguminous plants. After infection of plant cells, the free-living bacteria are converted into nitrogen-fixing bacteroids. The transformation includes an elongation of the cells and repeated chromosome replication (endoreduplication) without cytokinesis, leading to the multinucleate cells. It has been demonstrated that plant factors present in the nodules trigger endoreduplication ( Mergaert et al. , 2006 ).

So far, Rhizobium and M. tuberculosis are the only two examples for host cells–plant cells and human macrophages, respectively – capable of triggering bacterial replication frequency.

Concluding remarks

Much of what we know about the molecular mechanisms of the regulation of bacterial chromosome replication comes from studies of E. coli . So far, not many factors involved in the regulatory network of the replication of organisms other than E. coli have been identified. However, those identified have demonstrated that the diversity in the mechanisms involved in the regulation of replication initiation results from the different life cycles and lifestyles of the microorganisms. Comparative analysis of bacterial genomes together with expression profiles of their genes under different conditions and the application of high-throughput two-hybrid systems ( E. coli or yeast) for searching interacting proteins will allow us to identify new regulatory mechanisms in the near future. The elements involved in the novel mechanisms may provide valuable drug and vaccine targets against bacterial pathogens.

Acknowledgements

This work was supported by the Ministry of Science and Higher Education (grant 2P04A 054 29). D.J. acknowledges support from the Marie Curie Reintegration Grant MERG-6-CT-2005-014851. A. Z.-P. was supported by a Marie Curie Intra-European Fellowship within the 6th European Community Framework Programme. J.Z.-C., A.Z.-P. and D.J. acknowledge support from the Scientific and Technological International Cooperation Joint Project Polonium.

References

Akman
L
Yamashita
A
Watanabe
H
Oshima
K
Shiba
T
Hattori
M
Aksoy
S
(
2002
)
Genome sequence of the endocellular obligate symbiont of tsetse flies, Wigglesworthia glossinidia
.
Nat Genet
 
32
:
402
407
.
Baldus
JM
Green
BD
Youngman
P
Moran
CP
Jr
(
1994
)
Phosphorylation of Bacillus subtilis transcription factor Spo0A stimulates transcription from the spoIIG promoter by enhancing binding to weak 0A boxes
.
J Bacteriol
 
176
:
296
306
.
Boye
E
Lobner-Olesen
A
Skarstad
K
(
2000
)
Limiting DNA replication to once & only once
.
EMBO Rep
 
1
:
479
483
.
Brazhnik
P
Tyson
JJ
(
2006
)
Cell cycle control in bacteria and yeast: a case of convergent evolution?
Cell Cycle
 
5
:
522
529
.
Bruand
C
Velten
M
McGovern
S
Marsin
S
Serena
C
Ehrlich
D
Polard
P
(
2005
)
Functional interplay between the Bacillus subtilis DnaD and DnaB proteins essential for initiation and re-initiation of DNA replication
.
Mol Microbiol
 
55
:
1138
1150
.
Burkholder
WF
Kurtser
I
Grossman
AD
(
2001
)
Replication initiation proteins regulate a developmental checkpoint in Bacillus subtilis
.
Cell
 
104
:
269
279
.
Camara
JE
Breier
AM
Brendler
T
Austin
S
Cozzarelli
NR
Crooke
E
(
2005
)
Hda inactivation of DnaA is the predominant mechanism preventing hyperinitiation of Escherichia coli DNA replication
.
EMBO Reports
 
6
:
1
6
.
Carneiro
MJV
Zhang
W
Ioannou
C
Scott
DJ
Allen
S
Roberts
CJ
Soultanas
P
(
2006
)
The DNA-remodelling activity of DnaD is the sum of oligomerization and DNA-binding activities on separate domains
.
Mol Microbiol
 
60
:
917
924
.
Cassler
MR
Grimwade
JE
Leonard
AC
(
1995
)
Cell cycle-specific changes in nucleoprotein complexes at a chromosomal replication origin
.
EMBO J
 
14
:
5833
5841
.
Castilla-Liorente
V
Munoz-Espin
D
Villar
L
Salas
M
Meijer
WJJ
(
2006
)
Spo0A, the key transcriptional regulator for entrance into sporulation, is an inhibitor of DNA replication
.
EMBO J
 
25
:
3890
3899
.
Clarey
MG
Erzberger
JP
Grob
P
Leschziner
AE
Berger
JM
Nogales
E
Botchan
M
(
2006
)
Nucleotide-dependent conformational changes in the DnaA-like core of the origin recognition complex
.
Nat Struct Mol Biol
 
13
:
684
690
.
Collier
J
Murray
SR
Shapiro
L
(
2006
)
DnaA couples DNA replication and the expression of two cell cycle master regulators
.
EMBO J
 
25
:
346
356
.
Crosson
S
McAdams
H
Shapiro
L
(
2004
)
A genetic oscillator and the regulation of cell cycle progression in Caulobacter crescentus
.
Cell Cycle
 
10
:
1252
1254
.
Cunningham
EL
Berger
JM
(
2005
)
Unraveling the early steps of prokaryotic replication
.
Curr Opin Struct Biol
 
15
:
68
76
.
Davey
MJ
Jeruzalmi
D
Kuriyan
J
O'Donnell
M
(
2002
)
Motors and switches: AAA+machines within the replisome
.
Nat Rev Mol Cell Biol
 
3
:
826
835
.
Degnan
PH
Lazarus
AB
Wernegreen
JJ
(
2005
)
Genome sequence of Blochmannia pennsylvanicus indicates parallel evolutionary trends among bacterial mutualists of insects
.
Genome Res
 
8
:
1023
1033
.
Domain
IJ
Reisenauer
A
Shapiro
L
(
1999
)
Feedback control of a master bacterial cell-cycle regulator
.
Proc Natl Acad Sci USA
 
96
:
6648
6653
.
Duigou
S
Knudsen
KG
Skovgaard
O
Egan
ES
Løbner-Olesen
A
Waldor
MK
(
2006
)
Independent control of replication initiation of the two Vibrio cholerae chromosomes by DnaA and RctB
.
J Bacteriol
 
188
:
6419
6424
.
Egan
ES
Fogel
MA
Waldor
MK
(
2005
)
Divided genomes: negotiating the cell cycle in prokaryotes with multiple chromosomes
.
Mol Microbiol
 
56
:
1129
1138
.
Egan
ES
Waldor
MK
(
2003
)
Distinct replication requirements for the two Vibrio cholerae chromosomes
.
Cell
 
114
:
521
530
.
Egan
ES
Løbner-Olesen
A
Waldor
MK
(
2004
)
Synchronous replication initiation of the two Vibrio cholerae chromosomes
.
Curr Biol
 
14
:
R501
R502
.
Errington
J
Murray
H
Wu
LJ
(
2005
)
Diversity and redundancy in bacterial chromosome segregation mechanisms
.
Phil Trans R Soc B
 
360
:
497
505
.
Erzberger
JP
Pirruccello
MM
Berger
JM
(
2002
)
The structure of bacterial DnaA: implications for general mechanisms underlying DNA replication initiation
.
EMBO J
 
21
:
4763
4773
.
Erzberger
JP
Mott
ML
Berger
JM
(
2006
)
Structural basis for ATP-dependent DnaA assembly and replication-origin remodeling
.
Nat Struct Mol Biol
 
13
:
676
683
.
Felczak
MM
Simmons
LA
Kaguni
JM
(
2005
)
An essential tryptophan of Escherichia coli DnaA protein functions in oligomerization at the E. coli replication origin
.
J Biol Chem
 
280
:
24627
24633
.
Fol
M
Chauhan
A
Nair
NK
Malone
E
Moomey
M
Jagannath
C
Madiraju
MV
Rajagopalan
M
(
2006
)
Modulation of Mycobacterium tuberculosis proliferation by MtrA, an essential two-component response regulator
.
Mol Microbiol
 
60
:
643
657
.
Foster
J
Ganatra
M
Kamal
I
et al. (
2005
)
The Wolbachia genome of Brugia malayi : endosymbiont evolution within a human pathogenic nematode
.
PLoS Biol
 
3
e121
:
599
612
.
Fukuoka
T
Moriya
S
Yoshikawa
H
Ogasawara
N
(
1990
)
Purification and characterization of an initiation protein for chromosomal replication, DnaA, in Bacillus subtilis
.
J Biochem
 
107
:
732
739
.
Gil
R
Silva
FJ
Zientz
E
et al. (
2003
)
The genome sequence of Blochmannia floridanus: comparative analysis of reduced genomes
.
Proc Natl Acad Sci USA
 
100
:
9388
9393
.
Gon
S
Camara
JE
Klungsoyr
HK
Crooke
E
Skarstad
K
Beckwith
J
(
2006
)
A novel regulatory mechanism couples deoxyribonucleotide synthesis and DNA replication in Escherichia coli
.
EMBO J
 
25
:
1137
1147
.
Goranov
AI
Katz
L
Breier
AM
Burge
ChB
Grossman
AD
(
2005
)
A transcriptional response to replication status mediated by the conserved bacterial replication protein DnaA
.
Proc Natl Acad Sci USA
 
102
:
12932
12937
.
Gorbatyuk
B
Marczynski
GT
(
2005
)
Regulated degradation of chromosome replication proteins DnaA and CtrA in Caulobacter crescentus
.
Mol Microbiol
 
55
:
1233
1245
.
Han
JS
Park
JY
Lee
YS
Thony
B
Hwang
DS
(
1999
)
PhoB-dependent transcriptional activation of the iciA gene during starvation for phosphate in Escherichia coli
.
Mol Gen Genet
 
262
:
448
452
.
Hayashi
M
Ogura
Y
Harry
EJ
Ogasawara
N
Moriya
S
(
2005
)
Bacillus subtilis YabA is involved in determining the timing and synchrony of replication initiation
.
FEMS Microbiol Lett
 
247
:
73
79
.
Heidelberg
JF
Eisen
JA
Nelson
WC
et al. (
2000
)
DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae
.
Nature
 
406
:
469
470
.
Holtzendorff
J
Hung
D
Brende
P
Reisenauer
A
Viollier
PH
McAdams
HH
Shapiro
L
(
2004
)
Oscillating global regulators control the genetic circuit driving a bacterial cell cycle
.
Science
 
304
:
983
987
.
Holtzendorff
J
Reinhardt
J
Viollier
PH
(
2006
)
Cell cycle control by oscillating regulatory proteins in Caulobacter crescentus
.
BioEssays
 
28
:
355
361
.
Hoskisson
PA
Hutchings
MI
(
2006
)
MtrAB-LpqB: a conserved three-component system in actinobacteria?
Trends Microbiol
 
14
:
444
449
.
Hottes
AK
Shapiro
L
McAdams
HH
(
2005
)
DnaA coordinates replication initiation and cell cycle transcription in Caulobacter crescentus
.
Mol Microbiol
 
58
:
1340
1353
.
Hung
DY
Shapiro
L
(
2002
)
A signal transduction protein cues proteolytic events critical to Caulobacter cell cycle progression
.
Proc Natl Acad Sci USA
 
99
:
13160
13165
.
Hwang
DS
Kornberg
A
(
1992
)
Opening of the replication origin of Escherichia coli by DnaA protein with protein HU or IHF
.
J Biol Chem
 
267
:
23083
23086
.
Ishida
T
Akimitsu
N
Kashioka
T
Hatano
M
Kubota
T
Ogata
Y
Sekimizu
K
Katayama
T
(
2004
)
DiaA, a novel DnaA-binding protein, ensures the timely initiation of Escherichia coli chromosome replication
.
J Biol Chem
 
279
:
45546
45555
.
Iuchi
S
Weiner
L
(
1996
)
Cellular and molecular physiology of Escherichia coli in the adaptation to aerobic environments
.
J Biochem
 
120
:
1055
1063
.
Jakimowicz
D
Chater
K
Zakrzewska-Czerwińska
J
(
2002
)
The ParB protein of Streptomyces coelicolor A3(2) recognizes a cluster of parS sequences within the origin-proximal region of the linear chromosome
.
Mol Microbiol
 
45
:
1365
1377
.
Jakimowicz
D
Gust
B
Zakrzewska-Czerwińska
J
Chater
C
(
2005
)
Developmental-stage-specific assembly of ParB complexes in Streptomyces coelicolor hyphae
.
J Bacteriol
 
187
:
3572
3580
.
Jenal
U
Fuchs
T
(
1998
)
An essential protease involved in bacterial cell-cycle control
.
EMBO J
 
17
:
5658
5669
.
Jensen
RB
(
2006
)
Coordination between chromosome replication, segregation, and cell division in Caulobacter crescentus
.
J Bacteriol
 
188
:
2244
2253
.
Kaguni
JM
(
2006
)
DnaA: controlling the initiation of bacterial DNA replication and more
.
Annu Rev Microbiol
 
60
:
351
371
.
Kahng
LS
Shapiro
L
(
2001
)
The CcrM DNA methyltransferase of Agrobacterium tumefaciens is essential, and its activity is cell cycle regulated
.
J Bacteriol
 
181
:
3065
3075
.
Katayama
T
(
2001
)
Feedback controls restrain the initiation of Escherichia coli chromosomal replication
.
Mol Microbiol
 
41
:
9
17
.
Katayama
T
Kubota
T
Kurokawa
K
Crooke
E
Sekimizu
K
(
1998
)
The initiator function of DnaA protein is negatively regulated by the sliding clamp of the E. coli chromosomal replicase
.
Cell
 
94
:
61
71
.
Kato
J
(
2005
)
Regulatory network of the initiation of chromosomal replication in Escherichia coli
.
Critical Rev Biochem Mol Biol
 
40
:
331
342
.
Kato
J
Katayama
T.
(
2001
)
Hda, a novel DnaA-related protein, regulates the replication cycle in Escherichia coli
.
EMBO J
 
20
:
4253
4262
.
Kim
MS
Bae
SH
Yun
SH
et al. (
2005
)
Cnu, a novel oriC -binding protein of Escherichia coli
.
J Bacteriol
 
187
:
6998
7008
.
Kim
S
Dallmann
HG
McHenry
CS
Marians
KJ
(
1996
)
Coupling of a replicative polymerase and helicase: a tau–DnaB interaction mediates rapid replication fork movement
.
Cell
 
84
:
643
650
.
Kitagawa
R
Ozaki
T
Moriya
S
Ogawa
T
(
1998
)
Negative control of replication initiation by a novel chromosomal locus exhibiting exceptional affinity for Escherichia coli DnaA protein
.
Genes Dev
 
12
:
3032
3043
.
Konieczny
I.
(
2003
)
Strategies for helicase recruitment and loading in bacteria
.
EMBO Rep
 
4
:
37
41
.
Lee
DG
Bell
SP
(
2000
)
ATPase switches controlling DNA replication initiation
.
Curr Opin Cell Biol
 
3
:
280
285
.
Lee
PS
Grossman
AD
(
2006
)
The chromosome partitioning proteins Soj (ParA) and Spo0J (ParB) contribute to accurate chromosome partitioning, separation of replicated sister origins, and regulation of replication initiation in Bacillus subtilis
.
Mol Microbiol
 
60
:
853
869
.
Lee
PS
Lin
DCH
Shigeki
MS
Grossman
AD
(
2003
)
Effects of the chromosome partitioning protein Spo0J (ParB) on oriC positioning and replication initiation in Bacillus subtilis
.
J Bacteriol
 
185
:
1326
1337
.
Lee
YS
Han
JS
Jeon
Y
Hwang
DS
(
2001
)
The Arc two-component signal transduction system inhibits in vitro Escherichia coli chromosomal initiation
.
J Biol Chem
 
276
:
9917
9923
.
Leonard
AC
Grimwade
JE
(
2005
)
Building a bacterial orisome: emergence of new regulatory features for replication origin unwinding
.
Mol Microbiol
 
55
:
978
985
.
Lobner-Olesen
A
Skovgaard
O
Marinus
MG
(
2005
)
Dam methylation: coordinating cellular processes
.
Curr Opin Microbiol
 
8
:
154
160
.
Lu
Y-B
Ratnakar
PVAL
Mohanty
B.
Bastia
D
(
1996
)
Direct physical interaction between DnaG primase and DnaB helicase of Escherichia coli is necessary for optimal synthesis of primer RNA
.
Pro. Natl Aca Sci USA
 
93
:
12902
12907
.
Maaloe
O
Kjeldgaard
NO
(
1966
)
Control of Macromolecular Synthesis
  .
W.A. Benjamin, Inc.
, New York, NY.
Mackiewicz
P
Zakrzewska-Czerwiñska
J
Zawilak
A
Dudek
MR
Cebrat
S
(
2004
)
Where does bacterial replication start? Rules for predicting the oriC region
.
Nucl Acids Res
 
32
:
3781
3791
.
Madiraju
MVV
Moomey
M
Neuenschwander
PF
Muniruzzaman
S
Yamamoto
K
Grimwade
JE
Rajagopalan
M
(
2006
)
The intrinsic ATPase activity of Mycobacterium tuberculosis DnaA promotes its rapid oliogmerization on ori C
.
Mol Microbiol
 
59
:
1876
1890
.
Majka
J
Messer
W
Schrempf
H
Zakrzewska-Czerwińska
J
(
1997
)
Purification and characterization of the Streptomyces lividans initiator protein DnaA
.
J Bacteriol
 
179
:
2426
2432
.
Marczynski
GT
Shapiro
L
(
2002
)
Control of chromosome replication in Caulobacter crescentus
.
Annu Rev Microbiol
 
56
:
625
656
.
Margolin
W
Bernander
R
(
2004
)
How do prokaryotic cells cycle?
Curr Biol
 
14
:
R768
R770
.
McAdams
HH
Shapiro
L
(
2003
)
A bacterial cell-cycle regulatory network operating in time and space
.
Science
 
301
:
1874
1877
.
McGrath
PT
Viollier
P
McAdams
HH
(
2004
)
Setting the pace: mechanisms tying Caulobacter cell-cycle progression to macroscopic cellular events
.
Curr Opin Microbiol
 
7
:
192
197
.
Mergaert
P
Uchiumi
T
Alunni
B
et al. (
2006
)
Eukaryotic control on bacterial cell cycle and differentiation in the Rhizobium -legume symbiosis
.
Proc Natl Acad Sci USA
 
103
:
5230
5235
.
Messer
W
Weigel
C
(
1997
)
DnaA initiator–also a transcription factor
.
Mol Microbiol
 
24
:
1
6
.
Messer
W
(
2002
)
The bacterial replication initiator DnaA. DnaA & oriC, the bacterial mode to initiate DNA replication
.
FEMS Microbiol Rev
 
26
:
355
374
.
Moran
NA
(
2002
)
Microbial minimalism: genome reduction in bacterial pathogens
.
Cell
 
108
:
583
586
.
Moriya
S
Ima
Y
Hassan
AK
Ogasawara
N
(
1999
)
Regulation of initiation of Bacillus subtilis chromosome replication
.
Plasmid
 
41
:
17
29
.
Mukhopadhyay
S
Chattoraj
DK
(
2000
)
Replication-induced transcription of an autorepressed gene: the replication initiator gene of plasmid P1
.
Proc Natl Acad Sci USA
 
97
:
7142
7147
.
Murray
H
Ferreira
H
Errington
J
(
2006
)
The bacterial chromosome segregation protein Spo0J spreads along DNA from parS nucleation sites
.
Mol Microbiol
 
61
:
1352
1361
.
Noirot-Gros
MF
Dervyn
E
Wu
LJ
Mervelet
P
Errington
J
Ehrlich
SD
Noirot
P
(
2002
)
An expanded view of bacterial DNA replication
.
Proc Natl Acad Sci USA
 
99
:
8342
8347
.
Noirot-Gros
MF
Velten
M
Yoshimura
M
McGovern
S
Morimoto
T
Ehrlich
SD
Ogasawara
N
Polard
P
Noirot
P
(
2006
)
Functional dissection of YabA, a negative regulator of DNA replication initiation in Bacillus subtilis
.
Proc Natl Acad Sci USA
 
103
:
2368
2373
.
Ogura
Y
Imai
Y
Ogasawara
N
Moriya
S
(
2001
)
Autoregulation of the dnaA–dnaN operon and effects of DnaA protein levels on replication initiation in Bacillus subtilis
.
J Bacteriol
 
183
:
3833
3841
.
Ozaki
S
Fujimitsu
K
Kurumizaka
H
Katayama
T
(
2006
)
The DnaA homolog of the hyperthermophilic eubacterium Thermotoga maritima forms an open complex with a minimal 149-bp origin region in an ATP-dependent manner
.
Genes Cells
 
11
:
425
438
.
Park
K
Han
E
Paulsson
J
Chattoraj
DK
(
2001
)
Origin pairing (‘handcuffing’) as a mode of negative control of P1 plasmid copy number
.
EMBO J
 
20
:
7323
7332
.
Paulsson
J
Chattoraj
DK
(
2006
)
Origin inactivation in bacterial DNA replication control
.
Mol Microbiol
 
61
:
9
15
.
Quon
KC
Yang
B
Domian
IJ
Shapiro
L
Marczynski
GT
(
1998
)
Negative control of bacterial DNA replication by a cell cycle regulatory protein that binds at the chromosome origin
.
Proc Natl Acad Sci USA
 
95
:
120
125
.
Riber
L
Olsson
JA
Jensen
RB
Skovgaard
O
Dasgupta
S
Marinus
MG
Lobner-Olesen
A
(
2006
)
Hda mediated inactivation of the DnaA protein and dnaA gene autoregulation act in concert to ensure homeostatic maintenance of the Escherichia coli chromosome
.
Genes Dev
 
20
:
2121
2134
.
Robinson
NP
Bell
SD
(
2005
)
Origins of DNA replication in the three domains of life
.
FEBS J
 
272
:
3757
3766
.
Ruban-Osmialowska
B
Jakimowicz
D
Smulczyk-Krawczyszyn
A
Chater
KF
Zakrzewska-Czerwińska
J
(
2006
)
Replisome localization in vegetative and aerial hyphae of Streptomyces coelicolor
.
J Bacteriol
 
188
:
7311
7316
.
Ryan
VT
Grimwade
JE
Camara
JE
Crooke
E
Leonard
AC
(
2004
)
Escherichia coli prereplication complex assembly is regulated by dynamic interplay among Fis, IHF and DnaA
.
Mol Microbiol
 
51
:
1347
1359
.
Schaeffer
PM
Headlam
MJ
Dixon
NE
(
2005
)
Protein–protein interactions in the eubacterial replisome
.
IUBMB Life
 
57
:
5
12
.
Schaper
S
Nardmann
J
Lüder
G
Lurz
R
Speck
C
Messer
W
(
2000
)
Identification of the chromosomal replication origin from Thermus thermophilus and its interaction with the replication initiator DnaA
.
J Mol Biol
 
299
:
655
665
.
Siam
R
Marczynski
GT
(
2000
)
Cell cycle regulator phosphorylation stimulates two distinct modes of binding at a chromosome replication origin
.
EMBO J
 
19
:
1138
1147
.
Smulczyk-Krawczyszyn
A
Jakimowicz
D
Ruban-Ośmiałowska
B
Zawilak-Pawlik
A
Majka
J
Chater
K
Zakrzewska-Czerwińska
J
(
2006
)
Cluster of DnaA boxes involved in the regulation of Streptomyces chromosome replication: from in silico to in vivo studies
.
J Bacteriol
 
188
:
6184
6194
.
Speck
C
Messer
W
(
2001
)
Mechanism of origin unwinding: sequential binding of DnaA initiator protein to double-stranded and single-stranded DNA in the AT-rich region of the replication origin
.
EMBO J
 
20
:
1469
1476
.
Speck
C
Chen
Z
Li
H
Stillman
B
(
2005
)
ATPase-dependent cooperative binding of ORC and Cdc6 to origin DNA
.
Nat Struct Mol Biol
 
12
:
965
971
.
Stephens
C
Reisenauer
A
Wright
R
Shapiro
L
(
1996
)
A cell cycle-regulated bacterial DNA methyltransferase is essential for viability
.
Proc Natl Acad Sci USA
 
93
:
1210
1214
.
Stephens
CM
Zweiger
G
Shapiro
L
(
1995
)
Coordinate cell cycle control of a Caulobacter DNA methyltransferase and the flagellar genetic hierarchy
.
J Bacteriol
 
177
:
1662
1669
.
Tougu
K
Marians
KJ
(
1996
)
The extreme C terminus of primase is required for interaction with DnaB at the replication fork
.
J Biol Chem
 
271
:
21391
21397
.
Weigel
C
Schmidt
A
Ruckert
B
Lurz
R
Messer
W
(
1997
)
DnaA protein binding to individual DnaA boxes in the Escherichia coli replication origin, oriC
.
EMBO J
 
16
:
6574
6583
.
Weigel
C
Schmidt
A
Seitz
H
Tungler
D
Welzeck
M
Messer
W
(
1999
)
The N-terminus promotes oligomerization of the Escherichia coli initiator protein DnaA
.
Mol Microbiol
 
34
:
53
66
.
Wortinger
M
Sackett
MJ
Brun
YV
(
2000
)
CtrA mediates a DNA replication checkpoint that prevents cell division in Caulobacter crescentus
.
EMBO J
 
19
:
4503
4512
.
Wu
D
Daugherty
SC
Aken
SE
et al. (
2006
)
Metabolic complementarity and genomics of the dual bacterial symbiosis of sharpshooters
.
PLoS Biol
 
6
e188
:
1079
1092
.
Yamamoto
K
Muniruzzaman
S
Rajagopalan
M
Madiraju
MV
(
2002
)
Modulation of Mycobacterium tuberculosis DnaA protein-adenine-nucleotide interactions by acidic phospholipids
.
Biochem J
 
363
:
305
311
.
Zakrzewska-Czerwińska
J
Schrempf
H
(
1992
)
Characterization of an autonomously replicating region from the Streptomyces lividans chromosome
.
J Bacteriol
 
174
:
2688
2693
.
Zawilak-Pawlik
A
Kois
A
Majka
J
Jakimowicz
D
Smulczyk-Krawczyszyn
A
Messer
W
Zakrzewska-Czerwinska
J
(
2005
)
Architecture of bacterial replication initiation complexes: orisomes from four unrelated bacteria
.
Biochem J
 
389
:
471
481
.
Zhang
W
Allen
S
Roberts
CJ
Soultanas
P
(
2006
)
The Bacillus subtilis primosomal protein DnaD untwists supercoiled DNA
.
J Bacteriol
 
188
:
5487
5493
.
Zhang
W
Carneiro
MJVM
Turner
IJ
Allen
S
Roberts
CJ
Soultanas
P
(
2005
)
The Bacillus subtilis DnaD and DnaB proteins exhibit different DNA remodeling activities
.
J Mol Biol
 
351
:
66
75
.
Editor: Rafael Giraldo