Prokaryotic DNA replication

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Prokaryotic DNA Replication is the process by which a prokaryote duplicates its DNA into another copy that is passed on to daughter cells. [1] Although it is often studied in the model organism E. coli , other bacteria show many similarities. [2] Replication is bi-directional and originates at a single origin of replication (OriC). [3] It consists of three steps: Initiation, elongation, and termination. [4]

Contents

Bidirectional Theta type replication. Most circular bacterial chromosomes are replicated bidirectionally, starting at one point of origin and replicating in two directions away from the origin. This results in semiconservative replication, in which each new identical DNA molecule contains one template strand from the original molecule, shown as the solid lines, and one new strand, shown as the dotted lines. Circular bacterial chromosome replication.gif
Bidirectional Theta type replication. Most circular bacterial chromosomes are replicated bidirectionally, starting at one point of origin and replicating in two directions away from the origin. This results in semiconservative replication, in which each new identical DNA molecule contains one template strand from the original molecule, shown as the solid lines, and one new strand, shown as the dotted lines.

Initiation

All cells must finish DNA replication before they can proceed for cell division. Media conditions that support fast growth in bacteria also couples with shorter inter-initiation time in them, i.e. the doubling time in fast growing cells is less as compared to the slow growth. [5] In other words, it is possible that in fast growth conditions the grandmother cells starts replicating its DNA for grand daughter cell. For the same reason, the initiation of DNA replication is highly regulated. Bacterial origins regulate orisome assembly, a nuclei-protein complex assembled on the origin responsible for unwinding the origin and loading all the replication machinery. In E. coli, the direction for orisome assembly are built into a short stretch of nucleotide sequence called as origin of replication (oriC) which contains multiple binding sites for the initiator protein DnaA [6] (a highly homologous protein amongst bacterial kingdom). DnaA has four domains with each domain responsible for a specific task. [7] There are 11 DnaA binding sites/boxes on the E. coli origin of replication [6] out of which three boxes R1, R2 and R4 (which have a highly conserved 9 bp consensus sequence 5' - TTATC/ACACA [2] ) are high affinity DnaA boxes. They bind to DnaA-ADP and DnaA-ATP with equal affinities and are bound by DnaA throughout most of the cell cycle and forms a scaffold on which rest of the orisome assembles. The rest eight DnaA boxes are low affinity sites that preferentially bind to DnaA-ATP. [6] During initiation, DnaA bound to high affinity DnaA box R4 donates additional DnaA to the adjacent low affinity site and progressively fill all the low affinity DnaA boxes. [6] Filling of the sites changes origin conformation from its native state. It is hypothesized that DNA stretching by DnaA bound to the origin promotes strand separation which allows more DnaA to bind to the unwound region. [8] The DnaC helicase loader then interacts with the DnaA bound to the single-stranded DNA to recruit the DnaB helicase, [9] which will continue to unwind the DNA as the DnaG primase lays down an RNA primer and DNA Polymerase III holoenzyme begins elongation. [10]

Regulation

Chromosome replication in bacteria is regulated at the initiation stage. [2] DnaA-ATP is hydrolyzed into the inactive DnaA-ADP by RIDA (Regulatory Inactivation of DnaA), [11] and converted back to the active DnaA-ATP form by DARS (DnaA Reactivating Sequence, which is itself regulated by Fis and IHF). [12] [13] However, the main source of DnaA-ATP is synthesis of new molecules. [2] Meanwhile, several other proteins interact directly with the oriC sequence to regulate initiation, usually by inhibition. In E. coli these proteins include DiaA, [14] SeqA, [15] IciA, [2] HU, [9] and ArcA-P, [2] but they vary across other bacterial species. A few other mechanisms in E. coli that variously regulate initiation are DDAH (datA-Dependent DnaA Hydrolysis, which is also regulated by IHF), [16] inhibition of the dnaA gene (by the SeqA protein), [2] and reactivation of DnaA by the lipid membrane. [17]

Elongation

E coli replisome with a loop in lagging strand DNA E. coli replisome.png
E coli replisome with a loop in lagging strand DNA

Once priming is complete, DNA polymerase III holoenzyme is loaded into the DNA and replication begins. The catalytic mechanism of DNA polymerase III involves the use of two metal ions in the active site, and a region in the active site that can discriminate between deoxyribonucleotides and ribonucleotides. The metal ions are general divalent cations that help the 3' OH initiate a nucleophilic attack onto the alpha phosphate of the deoxyribonucleotide and orient and stabilize the negatively charged triphosphate on the deoxyribonucleotide. Nucleophilic attack by the 3' OH on the alpha phosphate releases pyrophosphate, which is then subsequently hydrolyzed (by inorganic phosphatase) into two phosphates. This hydrolysis drives DNA synthesis to completion.

Furthermore, DNA polymerase III must be able to distinguish between correctly paired bases and incorrectly paired bases. This is accomplished by distinguishing Watson-Crick base pairs through the use of an active site pocket that is complementary in shape to the structure of correctly paired nucleotides. This pocket has a tyrosine residue that is able to form van der Waals interactions with the correctly paired nucleotide. In addition, dsDNA (double stranded DNA) in the active site has a wider major groove and shallower minor groove that permits the formation of hydrogen bonds with the third nitrogen of purine bases and the second oxygen of pyrimidine bases. Finally, the active site makes extensive hydrogen bonds with the DNA backbone. These interactions result in the DNA polymerase III closing around a correctly paired base. If a base is inserted and incorrectly paired, these interactions could not occur due to disruptions in hydrogen bonding and van der Waals interactions.

DNA is read in the 3' → 5' direction, therefore, nucleotides are synthesized (or attached to the template strand) in the 5' → 3' direction. However, one of the parent strands of DNA is 3' → 5' while the other is 5' → 3'. To solve this, replication occurs in opposite directions. Heading towards the replication fork, the leading strand is synthesized in a continuous fashion, only requiring one primer. On the other hand, the lagging strand, heading away from the replication fork, is synthesized in a series of short fragments known as Okazaki fragments, consequently requiring many primers. The RNA primers of Okazaki fragments are subsequently degraded by RNase H and DNA Polymerase I (exonuclease), and the gaps (or nicks) are filled with deoxyribonucleotides and sealed by the enzyme ligase.

Rate of replication

The rate of DNA replication in a living cell was first measured as the rate of phage T4 DNA elongation in phage-infected E. coli. [18] During the period of exponential DNA increase at 37 °C, the rate was 749 nucleotides per second. The mutation rate per base pair per replication during phage T4 DNA synthesis is 1.7 per 108. [19]

Termination

Termination of DNA replication in E. coli is completed through the use of termination sequences and the Tus protein. These sequences allow the two replication forks to pass through in only one direction, but not the other.

DNA replication initially produces two catenated or linked circular DNA duplexes, each comprising one parental strand and one newly synthesised strand (by nature of semiconservative replication). This catenation can be visualised as two interlinked rings which cannot be separated. Topoisomerase 2 in E. coli unlinks or decatenates the two circular DNA duplexes by breaking the phosphodiester bonds present in two successive nucleotides of either parent DNA or newly formed DNA and thereafter the ligating activity ligates that broken DNA strand and so the two DNA get formed.

Other Prokaryotic replication models

The theta type replication has been already mentioned. There are other types of prokaryotic replication such as rolling circle replication and D-loop replication

Rolling Circle Replication

This is seen in bacterial conjugation where the same circulartemplate DNA rotates and around it the new strand develops.

Rolling circle replication Rolling circle.svg
Rolling circle replication

. When conjugation is initiated by a signal the relaxase enzyme creates a nick in one of the strands of the conjugative plasmid at the oriT. Relaxase may work alone or in a complex of over a dozen proteins known collectively as a relaxosome . In the F-plasmid system the relaxase enzyme is called TraI and the relaxosome consists of TraI, TraY, TraM and the integrated host factor IHF. The nicked strand, or T-strand, is then unwound from the unbroken strand and transferred to the recipient cell in a 5'-terminus to 3'-terminus direction. The remaining strand is replicated either independent of conjugative action (vegetative replication beginning at the oriV) or in concert with conjugation (conjugative replication similar to the rolling circle replication of lambda phage). Conjugative replication may require a second nick before successful transfer can occur. A recent report claims to have inhibited conjugation with chemicals that mimic an intermediate step of this second nicking event. [20]

D-loop replication

D-loop replication is mostly seen in organellar DNA, Where a triple stranded structure called displacement loop is formed. [21]

Related Research Articles

<span class="mw-page-title-main">DNA replication</span> Biological process

In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part of biological inheritance. This is essential for cell division during growth and repair of damaged tissues, while it also ensures that each of the new cells receives its own copy of the DNA. The cell possesses the distinctive property of division, which makes replication of DNA essential.

<span class="mw-page-title-main">Lambda phage</span> Bacteriophage that infects Escherichia coli

Enterobacteria phage λ is a bacterial virus, or bacteriophage, that infects the bacterial species Escherichia coli. It was discovered by Esther Lederberg in 1950. The wild type of this virus has a temperate life cycle that allows it to either reside within the genome of its host through lysogeny or enter into a lytic phase, during which it kills and lyses the cell to produce offspring. Lambda strains, mutated at specific sites, are unable to lysogenize cells; instead, they grow and enter the lytic cycle after superinfecting an already lysogenized cell.

<span class="mw-page-title-main">DNA polymerase</span> Form of DNA replication

A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create two identical DNA duplexes from a single original DNA duplex. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. These enzymes catalyze the chemical reaction

DNA primase is an enzyme involved in the replication of DNA and is a type of RNA polymerase. Primase catalyzes the synthesis of a short RNA segment called a primer complementary to a ssDNA template. After this elongation, the RNA piece is removed by a 5' to 3' exonuclease and refilled with DNA.

<span class="mw-page-title-main">DnaA</span>

DnaA is a protein that activates initiation of DNA replication in bacteria. Based on the Replicon Model, a positively active initiator molecule contacts with a particular spot on a circular chromosome called the replicator to start DNA replication. It is a replication initiation factor which promotes the unwinding of DNA at oriC. The DnaA proteins found in all bacteria engage with the DnaA boxes to start chromosomal replication. In addition to the DnaA protein, its concentration, binding to DnaA-boxes, and binding of ATP or ADP, we will cover the regulation of the DnaA gene, the unique characteristics of the DnaA gene expression, promoter strength, and translation efficiency. The onset of the initiation phase of DNA replication is determined by the concentration of DnaA. DnaA accumulates during growth and then triggers the initiation of replication. Replication begins with active DnaA binding to 9-mer (9-bp) repeats upstream of oriC. Binding of DnaA leads to strand separation at the 13-mer repeats. This binding causes the DNA to loop in preparation for melting open by the helicase DnaB.

<span class="mw-page-title-main">Okazaki fragments</span> Transient components of lagging strand of DNA

Okazaki fragments are short sequences of DNA nucleotides which are synthesized discontinuously and later linked together by the enzyme DNA ligase to create the lagging strand during DNA replication. They were discovered in the 1960s by the Japanese molecular biologists Reiji and Tsuneko Okazaki, along with the help of some of their colleagues.

<span class="mw-page-title-main">Origin of replication</span> Sequence in a genome

The origin of replication is a particular sequence in a genome at which replication is initiated. 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. This can either involve the replication of DNA in living organisms such as prokaryotes and eukaryotes, or that of DNA or RNA in viruses, such as double-stranded RNA viruses. 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. Although the specific replication origin organization structure and recognition varies from species to species, some common characteristics are shared.

<span class="mw-page-title-main">Pre-replication complex</span>

A pre-replication complex (pre-RC) is a protein complex that forms at the origin of replication during the initiation step of DNA replication. Formation of the pre-RC is required for DNA replication to occur. Complete and faithful replication of the genome ensures that each daughter cell will carry the same genetic information as the parent cell. Accordingly, formation of the pre-RC is a very important part of the cell cycle.

DNA gyrase, or simply gyrase, is an enzyme within the class of topoisomerase and is a subclass of Type II topoisomerases that reduces topological strain in an ATP dependent manner while double-stranded DNA is being unwound by elongating RNA-polymerase or by helicase in front of the progressing replication fork. The enzyme causes negative supercoiling of the DNA or relaxes positive supercoils. It does so by looping the template so as to form a crossing, then cutting one of the double helices and passing the other through it before releasing the break, changing the linking number by two in each enzymatic step. This process occurs in bacteria, whose single circular DNA is cut by DNA gyrase and the two ends are then twisted around each other to form supercoils. Gyrase is also found in eukaryotic plastids: it has been found in the apicoplast of the malarial parasite Plasmodium falciparum and in chloroplasts of several plants. Bacterial DNA gyrase is the target of many antibiotics, including nalidixic acid, novobiocin, albicidin, and ciprofloxacin.

A nick is a discontinuity in a double stranded DNA molecule where there is no phosphodiester bond between adjacent nucleotides of one strand typically through damage or enzyme action. Nicks allow DNA strands to untwist during replication, and are also thought to play a role in the DNA mismatch repair mechanisms that fix errors on both the leading and lagging daughter strands.

<span class="mw-page-title-main">T7 phage</span> Species of virus

Bacteriophage T7 is a bacteriophage, a virus that infects bacteria. It infects most strains of Escherichia coli and relies on these hosts to propagate. Bacteriophage T7 has a lytic life cycle, meaning that it destroys the cell it infects. It also possesses several properties that make it an ideal phage for experimentation: its purification and concentration have produced consistent values in chemical analyses; it can be rendered noninfectious by exposure to UV light; and it can be used in phage display to clone RNA binding proteins.

<span class="mw-page-title-main">DNA adenine methylase</span> Prokaryotic enzyme

DNA adenine methylase, (Dam methylase) (also site-specific DNA-methyltransferase (adenine-specific), EC 2.1.1.72, modification methylase, restriction-modification system) is an enzyme that adds a methyl group to the adenine of the sequence 5'-GATC-3' in newly synthesized DNA. Immediately after DNA synthesis, the daughter strand remains unmethylated for a short time. It is an orphan methyltransferase that is not part of a restriction-modification system and regulates gene expression. This enzyme catalyses the following chemical reaction

P1 is a temperate bacteriophage that infects Escherichia coli and some other bacteria. When undergoing a lysogenic cycle the phage genome exists as a plasmid in the bacterium unlike other phages that integrate into the host DNA. P1 has an icosahedral head containing the DNA attached to a contractile tail with six tail fibers. The P1 phage has gained research interest because it can be used to transfer DNA from one bacterial cell to another in a process known as transduction. As it replicates during its lytic cycle it captures fragments of the host chromosome. If the resulting viral particles are used to infect a different host the captured DNA fragments can be integrated into the new host's genome. This method of in vivo genetic engineering was widely used for many years and is still used today, though to a lesser extent. P1 can also be used to create the P1-derived artificial chromosome cloning vector which can carry relatively large fragments of DNA. P1 encodes a site-specific recombinase, Cre, that is widely used to carry out cell-specific or time-specific DNA recombination by flanking the target DNA with loxP sites.

<span class="mw-page-title-main">Eukaryotic DNA replication</span> DNA replication in eukaryotic organisms

Eukaryotic DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.

fis E. coli gene

fis is an E. coli gene encoding the Fis protein. The regulation of this gene is more complex than most other genes in the E. coli genome, as Fis is an important protein which regulates expression of other genes. It is supposed that fis is regulated by H-NS, IHF and CRP. It also regulates its own expression (autoregulation). Fis is one of the most abundant DNA binding proteins in Escherichia coli under nutrient-rich growth conditions.

An origin of transfer (oriT) is a short sequence ranging from 40-500 base pairs in length that is necessary for the transfer of DNA from a gram-negative bacterial donor to recipient during bacterial conjugation. The transfer of DNA is a critical component for antimicrobial resistance within bacterial cells and the oriT structure and mechanism within plasmid DNA is complementary to its function in bacterial conjugation. The first oriT to be identified and cloned was on the RK2 (IncP) conjugative plasmid, which was done by Guiney and Helinski in 1979.

<span class="mw-page-title-main">T7 DNA polymerase</span>

T7 DNA polymerase is an enzyme used during the DNA replication of the T7 bacteriophage. During this process, the DNA polymerase “reads” existing DNA strands and creates two new strands that match the existing ones. The T7 DNA polymerase requires a host factor, E. coli thioredoxin, in order to carry out its function. This helps stabilize the binding of the necessary protein to the primer-template to improve processivity by more than 100-fold, which is a feature unique to this enzyme. It is a member of the Family A DNA polymerases, which include E. coli DNA polymerase I and Taq DNA polymerase.

<span class="mw-page-title-main">Circular chromosome</span> Type of chromosome

A circular chromosome is a chromosome in bacteria, archaea, mitochondria, and chloroplasts, in the form of a molecule of circular DNA, unlike the linear chromosome of most eukaryotes.

<span class="mw-page-title-main">SeqA protein</span>

In molecular biology the SeqA protein is found in bacteria and archaea. The function of this protein is highly important in DNA replication. The protein negatively regulates the initiation of DNA replication at the origin of replication, in Escherichia coli, OriC. Additionally the protein plays a further role in sequestration. The importance of this protein is vital, without its help in DNA replication, cell division and other crucial processes could not occur. This protein domain is thought to be part of a much larger protein complex which includes other proteins such as SeqB.

<span class="mw-page-title-main">Bacterial DNA binding protein</span>

In molecular biology, bacterial DNA binding proteins are a family of small, usually basic proteins of about 90 residues that bind DNA and are known as histone-like proteins. Since bacterial binding proteins have a diversity of functions, it has been difficult to develop a common function for all of them. They are commonly referred to as histone-like and have many similar traits with the eukaryotic histone proteins. Eukaryotic histones package DNA to help it to fit in the nucleus, and they are known to be the most conserved proteins in nature. Examples include the HU protein in Escherichia coli, a dimer of closely related alpha and beta chains and in other bacteria can be a dimer of identical chains. HU-type proteins have been found in a variety of bacteria and archaea, and are also encoded in the chloroplast genome of some algae. The integration host factor (IHF), a dimer of closely related chains which is suggested to function in genetic recombination as well as in translational and transcriptional control is found in Enterobacteria and viral proteins including the African swine fever virus protein A104R.

References

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  10. ↑ Ozaki, Shogo; Noguchi, Yasunori; Hayashi, Yasuhisa; Miyazaki, Erika; Katayama, Tsutomu (26 October 2012). "Differentiation of the DnaA-oriC Subcomplex for DNA Unwinding in a Replication Initiation Complex". Journal of Biological Chemistry. 287 (44): 37458–37471. doi: 10.1074/jbc.M112.372052 . PMC   3481341 . PMID   22942281.
  11. ↑ Kato J, Katayama T (August 2001). "Hda, a novel DnaA-related protein, regulates the replicgation cycle in Escherichia coli". The EMBO Journal. 20 (15): 4253–62. doi:10.1093/emboj/20.15.4253. PMC   149159 . PMID   11483528.
  12. ↑ Fujimitsu K, Senriuchi T, Katayama T (May 2009). "Specific genomic sequences of E. coli promote replicational initiation by directly reactivating ADP-DnaA". Genes & Development. 23 (10): 1221–33. doi:10.1101/gad.1775809. PMC   2685538 . PMID   19401329.
  13. ↑ Kasho K, Fujimitsu K, Matoba T, Oshima T, Katayama T (December 2014). "Timely binding of IHF and Fis to DARS2 regulates ATP-DnaA production and replication initiation". Nucleic Acids Research. 42 (21): 13134–49. doi:10.1093/nar/gku1051. PMC   4245941 . PMID   25378325.
  14. ↑ Ishida T, Akimitsu N, Kashioka T, Hatano M, Kubota T, Ogata Y, Sekimizu K, Katayama T (October 2004). "DiaA, a novel DnaA-binding protein, ensures the timely initiation of Escherichia coli chromosome replication". The Journal of Biological Chemistry. 279 (44): 45546–55. doi: 10.1074/jbc.M402762200 . PMID   15326179.
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  19. ↑ Drake JW (1970) The Molecular Basis of Mutation. Holden-Day, San Francisco ISBN   0816224501 ISBN   978-0816224500.[ page needed ]
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