DNA polymerase

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DNA-directed DNA polymerase
DNA polymerase.png
3D structure of the DNA-binding helix-turn-helix motifs in human DNA polymerase beta (based on PDB file 7ICG)
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EC no. 2.7.7.7
CAS no. 9012-90-2
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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. [1] [2] [3] [4] [5] [6] These enzymes catalyze the chemical reaction

Contents

deoxynucleoside triphosphate + DNAn pyrophosphate + DNAn+1.

DNA polymerase adds nucleotides to the three prime (3')-end of a DNA strand, one nucleotide at a time. Every time a cell divides, DNA polymerases are required to duplicate the cell's DNA, so that a copy of the original DNA molecule can be passed to each daughter cell. In this way, genetic information is passed down from generation to generation.

Before replication can take place, an enzyme called helicase unwinds the DNA molecule from its tightly woven form, in the process breaking the hydrogen bonds between the nucleotide bases. This opens up or "unzips" the double-stranded DNA to give two single strands of DNA that can be used as templates for replication in the above reaction.

History

In 1956, Arthur Kornberg and colleagues discovered DNA polymerase I (Pol I), in Escherichia coli . They described the DNA replication process by which DNA polymerase copies the base sequence of a template DNA strand. Kornberg was later awarded the Nobel Prize in Physiology or Medicine in 1959 for this work. [7] DNA polymerase II was discovered by Thomas Kornberg (the son of Arthur Kornberg) and Malcolm E. Gefter in 1970 while further elucidating the role of Pol I in E. coli DNA replication. [8] Three more DNA polymerases have been found in E. coli, including DNA polymerase III (discovered in the 1970s) and DNA polymerases IV and V (discovered in 1999). [9]

Function

DNA polymerase moves along the old strand in the 3'-5' direction, creating a new strand having a 5'-3' direction. Replication fork.svg
DNA polymerase moves along the old strand in the 3'–5' direction, creating a new strand having a 5'–3' direction.
DNA polymerase with proofreading ability DNA polymerase.svg
DNA polymerase with proofreading ability

The main function of DNA polymerase is to synthesize DNA from deoxyribonucleotides, the building blocks of DNA. The DNA copies are created by the pairing of nucleotides to bases present on each strand of the original DNA molecule. This pairing always occurs in specific combinations, with cytosine along with guanine, and thymine along with adenine, forming two separate pairs, respectively. By contrast, RNA polymerases synthesize RNA from ribonucleotides from either RNA or DNA.[ citation needed ]

When synthesizing new DNA, DNA polymerase can add free nucleotides only to the 3' end of the newly forming strand. This results in elongation of the newly forming strand in a 5'–3' direction.[ citation needed ]

It is important to note that the directionality of the newly forming strand (the daughter strand) is opposite to the direction in which DNA polymerase moves along the template strand. Since DNA polymerase requires a free 3' OH group for initiation of synthesis, it can synthesize in only one direction by extending the 3' end of the preexisting nucleotide chain. Hence, DNA polymerase moves along the template strand in a 3'–5' direction, and the daughter strand is formed in a 5'–3' direction. This difference enables the resultant double-strand DNA formed to be composed of two DNA strands that are antiparallel to each other.[ citation needed ]

The function of DNA polymerase is not quite perfect, with the enzyme making about one mistake for every billion base pairs copied. Error correction is a property of some, but not all DNA polymerases. This process corrects mistakes in newly synthesized DNA. When an incorrect base pair is recognized, DNA polymerase moves backwards by one base pair of DNA. The 3'–5' exonuclease activity of the enzyme allows the incorrect base pair to be excised (this activity is known as proofreading ). Following base excision, the polymerase can re-insert the correct base and replication can continue forwards. This preserves the integrity of the original DNA strand that is passed onto the daughter cells.

Fidelity is very important in DNA replication. Mismatches in DNA base pairing can potentially result in dysfunctional proteins and could lead to cancer. Many DNA polymerases contain an exonuclease domain, which acts in detecting base pair mismatches and further performs in the removal of the incorrect nucleotide to be replaced by the correct one. [10] The shape and the interactions accommodating the Watson and Crick base pair are what primarily contribute to the detection or error. Hydrogen bonds play a key role in base pair binding and interaction. The loss of an interaction, which occurs at a mismatch, is said to trigger a shift in the balance, for the binding of the template-primer, from the polymerase, to the exonuclease domain. In addition, an incorporation of a wrong nucleotide causes a retard in DNA polymerization. This delay gives time for the DNA to be switched from the polymerase site to the exonuclease site. Different conformational changes and loss of interaction occur at different mismatches. In a purine:pyrimidine mismatch there is a displacement of the pyrimidine towards the major groove and the purine towards the minor groove. Relative to the shape of DNA polymerase's binding pocket, steric clashes occur between the purine and residues in the minor groove, and important van der Waals and electrostatic interactions are lost by the pyrimidine. [11] Pyrimidine:pyrimidine and purine:purine mismatches present less notable changes since the bases are displaced towards the major groove, and less steric hindrance is experienced. However, although the different mismatches result in different steric properties, DNA polymerase is still able to detect and differentiate them so uniformly and maintain fidelity in DNA replication. [12] DNA polymerization is also critical for many mutagenesis processes and is widely employed in biotechnologies.

Structure

The known DNA polymerases have highly conserved structure, which means that their overall catalytic subunits vary very little from species to species, independent of their domain structures. Conserved structures usually indicate important, irreplaceable functions of the cell, the maintenance of which provides evolutionary advantages. The shape can be described as resembling a right hand with thumb, finger, and palm domains. The palm domain appears to function in catalyzing the transfer of phosphoryl groups in the phosphoryl transfer reaction. DNA is bound to the palm when the enzyme is active. This reaction is believed to be catalyzed by a two-metal-ion mechanism. The finger domain functions to bind the nucleoside triphosphates with the template base. The thumb domain plays a potential role n the processivity, translocation, and positioning of the DNA. [13]

Processivity

DNA polymerase's rapid catalysis due to its processie nature. Processivity is a characteristic of enzymes that function on polymeric substrates. In the case of DNA polymerase, the degree of processivity refers to the average number of nucleotides added each time the enzyme binds a template. The average DNA polymerase requires about one second locating and binding a primer/template junction. Once it is bound, a nonprocessive DNA polymerase adds nucleotides at a rate of one nucleotide per second. [14] :207–208 Processive DNA polymerases, however, add multiple nucleotides per second, drastically increasing the rate of DNA synthesis. The degree of processivity is directly proportional to the rate of DNA synthesis. The rate of DNA synthesis in a living cell was first determined as the rate of phage T4 DNA elongation in phage infected E. coli. During the period of exponential DNA increase at 37 °C, the rate was 749 nucleotides per second. [15]

DNA polymerase's ability to slide along the DNA template allows increased processivity. There is a dramatic increase in processivity at the replication fork. This increase is facilitated by the DNA polymerase's association with proteins known as the sliding DNA clamp. The clamps are multiple protein subunits associated in the shape of a ring. Using the hydrolysis of ATP, a class of proteins known as the sliding clamp loading proteins open up the ring structure of the sliding DNA clamps allowing binding to and release from the DNA strand. Protein–protein interaction with the clamp prevents DNA polymerase from diffusing from the DNA template, thereby ensuring that the enzyme binds the same primer/template junction and continues replication. [14] :207–208 DNA polymerase changes conformation, increasing affinity to the clamp when associated with it and decreasing affinity when it completes the replication of a stretch of DNA to allow release from the clamp.[ citation needed ]

DNA polymerase processivity has been studied with in vitro single-molecule experiments (namely, optical tweezers and magnetic tweezers) have revealed the synergies between DNA polymerases and other molecules of the replisome (helicases and SSBs) and with the DNA replication fork. [16] These results have led to the development of synergetic kinetic models for DNA replication describing the resulting DNA polymerase processivity increase. [16]

Variation across species

DNA polymerase family A
PDB 2hht EBI.jpg
c:o6-methyl-guanine pair in the polymerase-2 basepair position
Identifiers
SymbolDNA_pol_A
Pfam PF00476
InterPro IPR001098
SMART -
PROSITE PDOC00412
SCOP2 1dpi / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
DNA polymerase family B
PDB 2dy4 EBI.jpg
crystal structure of rb69 gp43 in complex with dna containing thymine glycol
Identifiers
SymbolDNA_pol_B
Pfam PF00136
Pfam clan CL0194
InterPro IPR006134
PROSITE PDOC00107
SCOP2 1noy / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
DNA polymerase type B, organellar and viral
PDB 1xhz EBI.jpg
phi29 dna polymerase, orthorhombic crystal form, ssdna complex
Identifiers
SymbolDNA_pol_B_2
Pfam PF03175
Pfam clan CL0194
InterPro IPR004868
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Based on sequence homology, DNA polymerases can be further subdivided into seven different families: A, B, C, D, X, Y, and RT.

Some viruses also encode special DNA polymerases, such as Hepatitis B virus DNA polymerase. These may selectively replicate viral DNA through a variety of mechanisms. Retroviruses encode an unusual DNA polymerase called reverse transcriptase, which is an RNA-dependent DNA polymerase (RdDp). It polymerizes DNA from a template of RNA.

Family [17] Types of DNA polymeraseTaxaExamplesFeature
AReplicative and Repair PolymerasesEukaryotic and ProkaryoticT7 DNA polymerase, Pol I, Pol γ, θ, and νTwo exonuclease domains (3'-5' and 5'-3')
BReplicative and Repair PolymerasesEukaryotic and ProkaryoticPol II, Pol B, Pol ζ, Pol α, δ, and ε3'-5 exonuclease (proofreading); some viral polymerases use protein primers
CReplicative PolymerasesProkaryoticPol III3'-5 exonuclease (proofreading)
DReplicative Polymerases Euryarchaeota PolD (DP1/DP2 heterodimer) [18] No "hand" feature, double barrel RNA polymerase-like; 3'-5 exonuclease (proofreading)
XReplicative and Repair PolymerasesEukaryoticPol β, Pol σ, Pol λ, Pol μ, and terminal deoxynucleotidyl transferase template optional; 5' phosphatase (only Pol β); weak "hand" feature
YReplicative and Repair PolymerasesEukaryotic and ProkaryoticPol ι, Pol κ, Pol η, [19] Pol IV, and Pol VTranslesion synthesis [20]
RTReplicative and Repair PolymerasesViruses, Retroviruses, and Eukaryotic Telomerase, Hepatitis B virusRNA-dependent

Prokaryotic polymerase

Prokaryotic polymerases exist in two forms: core polymerase and holoenzyme. Core polymerase synthesizes DNA from the DNA template but it cannot initiate the synthesis alone or accurately. Holoenzyme accurately initiates synthesis.

Pol I

Prokaryotic family A polymerases include the DNA polymerase I (Pol I) enzyme, which is encoded by the polA gene and ubiquitous among prokaryotes. This repair polymerase is involved in excision repair with both 3'–5' and 5'–3' exonuclease activity and processing of Okazaki fragments generated during lagging strand synthesis. [21] Pol I is the most abundant polymerase, accounting for >95% of polymerase activity in E. coli; yet cells lacking Pol I have been found suggesting Pol I activity can be replaced by the other four polymerases. Pol I adds ~15-20 nucleotides per second, thus showing poor processivity. Instead, Pol I starts adding nucleotides at the RNA primer:template junction known as the origin of replication (ori). Approximately 400 bp downstream from the origin, the Pol III holoenzyme is assembled and takes over replication at a highly processive speed and nature. [22]

Taq polymerase is a heat-stable enzyme of this family that lacks proofreading ability. [23]

Pol II

DNA polymerase II is a family B polymerase encoded by the polB gene. Pol II has 3'–5' exonuclease activity and participates in DNA repair, replication restart to bypass lesions, and its cell presence can jump from ~30-50 copies per cell to ~200–300 during SOS induction. Pol II is also thought to be a backup to Pol III as it can interact with holoenzyme proteins and assume a high level of processivity. The main role of Pol II is thought to be the ability to direct polymerase activity at the replication fork and help stalled Pol III bypass terminal mismatches. [24]

Pfu DNA polymerase is a heat-stable enzyme of this family found in the hyperthermophilic archaeon Pyrococcus furiosus . [25] Detailed classification divides family B in archaea into B1, B2, B3, in which B2 is a group of pseudoenzymes. Pfu belongs to family B3. Others PolBs found in archaea are part of "Casposons", Cas1-dependent transposons. [26] Some viruses (including Φ29 DNA polymerase) and mitochondrial plasmids carry polB as well. [27]

Pol III

DNA polymerase III holoenzyme is the primary enzyme involved in DNA replication in E. coli and belongs to family C polymerases. It consists of three assemblies: the pol III core, the beta sliding clamp processivity factor, and the clamp-loading complex. The core consists of three subunits: α, the polymerase activity hub, ɛ, exonucleolytic proofreader, and θ, which may act as a stabilizer for ɛ. The beta sliding clamp processivity factor is also present in duplicate, one for each core, to create a clamp that encloses DNA allowing for high processivity. [28] The third assembly is a seven-subunit (τ2γδδχψ) clamp loader complex.

The old textbook "trombone model" depicts an elongation complex with two equivalents of the core enzyme at each replication fork (RF), one for each strand, the lagging and leading. [24] However, recent evidence from single-molecule studies indicates an average of three stoichiometric equivalents of core enzyme at each RF for both Pol III and its counterpart in B. subtilis, PolC. [29] In-cell fluorescent microscopy has revealed that leading strand synthesis may not be completely continuous, and Pol III* (i.e., the holoenzyme α, ε, τ, δ and χ subunits without the ß2 sliding clamp) has a high frequency of dissociation from active RFs. [30] In these studies, the replication fork turnover rate was about 10s for Pol III*, 47s for the ß2 sliding clamp, and 15m for the DnaB helicase. This suggests that the DnaB helicase may remain stably associated at RFs and serve as a nucleation point for the competent holoenzyme. In vitro single-molecule studies have shown that Pol III* has a high rate of RF turnover when in excess, but remains stably associated with replication forks when concentration is limiting. [30] Another single-molecule study showed that DnaB helicase activity and strand elongation can proceed with decoupled, stochastic kinetics. [30]

Pol IV

In E. coli, DNA polymerase IV (Pol IV) is an error-prone DNA polymerase involved in non-targeted mutagenesis. [31] Pol IV is a Family Y polymerase expressed by the dinB gene that is switched on via SOS induction caused by stalled polymerases at the replication fork. During SOS induction, Pol IV production is increased tenfold and one of the functions during this time is to interfere with Pol III holoenzyme processivity. This creates a checkpoint, stops replication, and allows time to repair DNA lesions via the appropriate repair pathway. [32] Another function of Pol IV is to perform translesion synthesis at the stalled replication fork like, for example, bypassing N2-deoxyguanine adducts at a faster rate than transversing undamaged DNA. Cells lacking the dinB gene have a higher rate of mutagenesis caused by DNA damaging agents. [33]

Pol V

DNA polymerase V (Pol V) is a Y-family DNA polymerase that is involved in SOS response and translesion synthesis DNA repair mechanisms. [34] Transcription of Pol V via the umuDC genes is highly regulated to produce only Pol V when damaged DNA is present in the cell generating an SOS response. Stalled polymerases causes RecA to bind to the ssDNA, which causes the LexA protein to autodigest. LexA then loses its ability to repress the transcription of the umuDC operon. The same RecA-ssDNA nucleoprotein posttranslationally modifies the UmuD protein into UmuD' protein. UmuD and UmuD' form a heterodimer that interacts with UmuC, which in turn activates umuC's polymerase catalytic activity on damaged DNA. [35] In E. coli, a polymerase "tool belt" model for switching pol III with pol IV at a stalled replication fork, where both polymerases bind simultaneously to the β-clamp, has been proposed. [36] However, the involvement of more than one TLS polymerase working in succession to bypass a lesion has not yet been shown in E. coli. Moreover, Pol IV can catalyze both insertion and extension with high efficiency, whereas pol V is considered the major SOS TLS polymerase. One example is the bypass of intra strand guanine thymine cross-link where it was shown on the basis of the difference in the mutational signatures of the two polymerases, that pol IV and pol V compete for TLS of the intra-strand crosslink. [36]

Family D

Structures of archaeal polD and eukaryotic Pola. Not only is the general topology conserved, the two also share a bifunctional primase-and-PCNA-binding PIP-box sequence on the C-terminus, similar to both eukaryotic Pola and Pole. Shared primase-binding peptide in archaeal PolD and eukaryotic Pola.pdf
Structures of archaeal polD and eukaryotic Polα. Not only is the general topology conserved, the two also share a bifunctional primase-and-PCNA-binding PIP-box sequence on the C-terminus, similar to both eukaryotic Polα and Polε.

In 1998, the family D of DNA polymerase was discovered in Pyrococcus furiosus and Methanococcus jannaschii . [38] The PolD complex is a heterodimer of two chains, each encoded by DP1 (small proofreading) and DP2 (large catalytic). Unlike other DNA polymerases, the structure and mechanism of the DP2 catalytic core resemble that of multi-subunit RNA polymerases. The DP1-DP2 interface resembles that of Eukaryotic Class B polymerase zinc finger and its small subunit. [18] DP1, a Mre11-like exonuclease, [39] is likely the precursor of small subunit of Pol α and ε, providing proofreading capabilities now lost in Eukaryotes. [26] Its N-terminal HSH domain is similar to AAA proteins, especially Pol III subunit δ and RuvB, in structure. [40] DP2 has a Class II KH domain. [18] Pyrococcus abyssi polD is more heat-stable and more accurate than Taq polymerase, but has not yet been commercialized. [41] It has been proposed that family D DNA polymerase was the first to evolve in cellular organisms and that the replicative polymerase of the Last Universal Cellular Ancestor (LUCA) belonged to family D. [42]

Eukaryotic DNA polymerase

Polymerases β, λ, σ, μ (beta, lambda, sigma, mu) and TdT

Family X polymerases contain the well-known eukaryotic polymerase pol β (beta), as well as other eukaryotic polymerases such as Pol σ (sigma), Pol λ (lambda), Pol μ (mu), and Terminal deoxynucleotidyl transferase (TdT). Family X polymerases are found mainly in vertebrates, and a few are found in plants and fungi. These polymerases have highly conserved regions that include two helix-hairpin-helix motifs that are imperative in the DNA-polymerase interactions. One motif is located in the 8 kDa domain that interacts with downstream DNA and one motif is located in the thumb domain that interacts with the primer strand. Pol β, encoded by POLB gene, is required for short-patch base excision repair, a DNA repair pathway that is essential for repairing alkylated or oxidized bases as well as abasic sites. Pol λ and Pol μ, encoded by the POLL and POLM genes respectively, are involved in non-homologous end-joining, a mechanism for rejoining DNA double-strand breaks due to hydrogen peroxide and ionizing radiation, respectively. TdT is expressed only in lymphoid tissue, and adds "n nucleotides" to double-strand breaks formed during V(D)J recombination to promote immunological diversity. [43]

Polymerases α, δ and ε (alpha, delta, and epsilon)

Pol α (alpha), Pol δ (delta), and Pol ε (epsilon) are members of Family B Polymerases and are the main polymerases involved with nuclear DNA replication. Pol α complex (pol α-DNA primase complex) consists of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the small and the large primase subunits PRIM1 and PRIM2 respectively. Once primase has created the RNA primer, Pol α starts replication elongating the primer with ~20 nucleotides. [44] Due to its high processivity, Pol δ takes over the leading and lagging strand synthesis from Pol α. [14] :218–219 Pol δ is expressed by genes POLD1, creating the catalytic subunit, POLD2, POLD3, and POLD4 creating the other subunits that interact with Proliferating Cell Nuclear Antigen (PCNA), which is a DNA clamp that allows Pol δ to possess processivity. [45] Pol ε is encoded by the POLE1, the catalytic subunit, POLE2, and POLE3 gene. It has been reported that the function of Pol ε is to extend the leading strand during replication, [46] [47] while Pol δ primarily replicates the lagging strand; however, recent evidence suggested that Pol δ might have a role in replicating the leading strand of DNA as well. [48] Pol ε's C-terminus "polymerase relic" region, despite being unnecessary for polymerase activity, [49] is thought to be essential to cell vitality. The C-terminus region is thought to provide a checkpoint before entering anaphase, provide stability to the holoenzyme, and add proteins to the holoenzyme necessary for initiation of replication. [50] Pol ε has a larger "palm" domain that provides high processivity independently of PCNA. [49]

Compared to other Family B polymerases, the DEDD exonuclease family responsible for proofreading is inactivated in Pol α. [26] Pol ε is unique in that it has two zinc finger domains and an inactive copy of another family B polymerase in its C-terminal. The presence of this zinc finger has implications in the origins of Eukaryota, which in this case is placed into the Asgard group with archaeal B3 polymerase. [51]

Polymerases η, ι and κ (eta, iota, and kappa)

Pol η (eta), Pol ι (iota), and Pol κ (kappa), are Family Y DNA polymerases involved in the DNA repair by translation synthesis and encoded by genes POLH, POLI, and POLK respectively. Members of Family Y have five common motifs to aid in binding the substrate and primer terminus and they all include the typical right hand thumb, palm and finger domains with added domains like little finger (LF), polymerase-associated domain (PAD), or wrist. The active site, however, differs between family members due to the different lesions being repaired. Polymerases in Family Y are low-fidelity polymerases, but have been proven to do more good than harm as mutations that affect the polymerase can cause various diseases, such as skin cancer and Xeroderma Pigmentosum Variant (XPS). The importance of these polymerases is evidenced by the fact that gene encoding DNA polymerase η is referred as XPV, because loss of this gene results in the disease Xeroderma Pigmentosum Variant. Pol η is particularly important for allowing accurate translesion synthesis of DNA damage resulting from ultraviolet radiation. The functionality of Pol κ is not completely understood, but researchers have found two probable functions. Pol κ is thought to act as an extender or an inserter of a specific base at certain DNA lesions. All three translesion synthesis polymerases, along with Rev1, are recruited to damaged lesions via stalled replicative DNA polymerases. There are two pathways of damage repair leading researchers to conclude that the chosen pathway depends on which strand contains the damage, the leading or lagging strand. [52]

Polymerases Rev1 and ζ (zeta)

Pol ζ another B family polymerase, is made of two subunits Rev3, the catalytic subunit, and Rev7 (MAD2L2), which increases the catalytic function of the polymerase, and is involved in translesion synthesis. Pol ζ lacks 3' to 5' exonuclease activity, is unique in that it can extend primers with terminal mismatches. Rev1 has three regions of interest in the BRCT domain, ubiquitin-binding domain, and C-terminal domain and has dCMP transferase ability, which adds deoxycytidine opposite lesions that would stall replicative polymerases Pol δ and Pol ε. These stalled polymerases activate ubiquitin complexes that in turn disassociate replication polymerases and recruit Pol ζ and Rev1. Together Pol ζ and Rev1 add deoxycytidine and Pol ζ extends past the lesion. Through a yet undetermined process, Pol ζ disassociates and replication polymerases reassociate and continue replication. Pol ζ and Rev1 are not required for replication, but loss of REV3 gene in budding yeast can cause increased sensitivity to DNA-damaging agents due to collapse of replication forks where replication polymerases have stalled. [53]

Telomerase

Telomerase is a ribonucleoprotein which functions to replicate ends of linear chromosomes since normal DNA polymerase cannot replicate the ends, or telomeres. The single-strand 3' overhang of the double-strand chromosome with the sequence 5'-TTAGGG-3' recruits telomerase. Telomerase acts like other DNA polymerases by extending the 3' end, but, unlike other DNA polymerases, telomerase does not require a template. The TERT subunit, an example of a reverse transcriptase, uses the RNA subunit to form the primer–template junction that allows telomerase to extend the 3' end of chromosome ends. The gradual decrease in size of telomeres as the result of many replications over a lifetime are thought to be associated with the effects of aging. [14] :248–249

Polymerases γ, θ and ν (gamma, theta and nu)

Pol γ (gamma), Pol θ (theta), and Pol ν (nu) are Family A polymerases. Pol γ, encoded by the POLG gene, was long thought to be the only mitochondrial polymerase. However, recent research shows that at least Pol β (beta), a Family X polymerase, is also present in mitochondria. [54] [55] Any mutation that leads to limited or non-functioning Pol γ has a significant effect on mtDNA and is the most common cause of autosomal inherited mitochondrial disorders. [56] Pol γ contains a C-terminus polymerase domain and an N-terminus 3'–5' exonuclease domain that are connected via the linker region, which binds the accessory subunit. The accessory subunit binds DNA and is required for processivity of Pol γ. Point mutation A467T in the linker region is responsible for more than one-third of all Pol γ-associated mitochondrial disorders. [57] While many homologs of Pol θ, encoded by the POLQ gene, are found in eukaryotes, its function is not clearly understood. The sequence of amino acids in the C-terminus is what classifies Pol θ as Family A polymerase, although the error rate for Pol θ is more closely related to Family Y polymerases. Pol θ extends mismatched primer termini and can bypass abasic sites by adding a nucleotide. It also has Deoxyribophosphodiesterase (dRPase) activity in the polymerase domain and can show ATPase activity in close proximity to ssDNA. [58] Pol ν (nu) is considered to be the least effective of the polymerase enzymes. [59] However, DNA polymerase nu plays an active role in homology repair during cellular responses to crosslinks, fulfilling its role in a complex with helicase. [59]

Plants use two Family A polymerases to copy both the mitochondrial and plastid genomes. They are more similar to bacterial Pol I than they are to mammalian Pol γ. [60]

Reverse transcriptase

Retroviruses encode an unusual DNA polymerase called reverse transcriptase, which is an RNA-dependent DNA polymerase (RdDp) that synthesizes DNA from a template of RNA. The reverse transcriptase family contain both DNA polymerase functionality and RNase H functionality, which degrades RNA base-paired to DNA. An example of a retrovirus is HIV. [14] Reverse transcriptase is commonly employed in amplification of RNA for research purposes. Using an RNA template, PCR can utilize reverse transcriptase, creating a DNA template. This new DNA template can then be used for typical PCR amplification. The products of such an experiment are thus amplified PCR products from RNA. [9]

Each HIV retrovirus particle contains two RNA genomes, but, after an infection, each virus generates only one provirus. [61] After infection, reverse transcription is accompanied by template switching between the two genome copies (copy choice recombination). [61] From 5 to 14 recombination events per genome occur at each replication cycle. [62] Template switching (recombination) appears to be necessary for maintaining genome integrity and as a repair mechanism for salvaging damaged genomes. [63] [61]

Bacteriophage T4 DNA polymerase

Bacteriophage (phage) T4 encodes a DNA polymerase that catalyzes DNA synthesis in a 5' to 3' direction. [64] The phage polymerase also has an exonuclease activity that acts in a 3' to 5' direction, [65] and this activity is employed in the proofreading and editing of newly inserted bases. [66] A phage mutant with a temperature sensitive DNA polymerase, when grown at permissive temperatures, was observed to undergo recombination at frequencies that are about two-fold higher than that of wild-type phage. [67]

It was proposed that a mutational alteration in the phage DNA polymerase can stimulate template strand switching (copy choice recombination) during replication. [67]

See also

Related Research Articles

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<span class="mw-page-title-main">Polymerase</span> Class of enzymes which synthesize nucleic acid chains or polymers

In biochemistry, a polymerase is an enzyme that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by copying a DNA template strand using base-pairing interactions or RNA by half ladder replication.

<span class="mw-page-title-main">RNA polymerase</span> Enzyme that synthesizes RNA from DNA

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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">DNA polymerase I</span> Family of enzymes

DNA polymerase I is an enzyme that participates in the process of prokaryotic DNA replication. Discovered by Arthur Kornberg in 1956, it was the first known DNA polymerase. It was initially characterized in E. coli and is ubiquitous in prokaryotes. In E. coli and many other bacteria, the gene that encodes Pol I is known as polA. The E. coli Pol I enzyme is composed of 928 amino acids, and is an example of a processive enzyme — it can sequentially catalyze multiple polymerisation steps without releasing the single-stranded template. The physiological function of Pol I is mainly to support repair of damaged DNA, but it also contributes to connecting Okazaki fragments by deleting RNA primers and replacing the ribonucleotides with DNA.

<span class="mw-page-title-main">DNA polymerase III holoenzyme</span> Primary enzyme complex involved in prokaryotic DNA replication

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In molecular biology and biochemistry, processivity is an enzyme's ability to catalyze "consecutive reactions without releasing its substrate".

<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">Exonuclease</span> Class of enzymes; type of nuclease

Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is the endonuclease, which cleaves phosphodiester bonds in the middle (endo) of a polynucleotide chain. Eukaryotes and prokaryotes have three types of exonucleases involved in the normal turnover of mRNA: 5′ to 3′ exonuclease (Xrn1), which is a dependent decapping protein; 3′ to 5′ exonuclease, an independent protein; and poly(A)-specific 3′ to 5′ exonuclease.

<span class="mw-page-title-main">RNA polymerase II</span> Protein complex that transcribes DNA

RNA polymerase II is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryotic cells. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase. A wide range of transcription factors are required for it to bind to upstream gene promoters and begin transcription.

<span class="mw-page-title-main">DNA polymerase II</span> Class of enzymes

DNA polymerase II is a prokaryotic DNA-dependent DNA polymerase encoded by the PolB gene.

<span class="mw-page-title-main">Replisome</span> Molecular complex

The replisome is a complex molecular machine that carries out replication of DNA. The replisome first unwinds double stranded DNA into two single strands. For each of the resulting single strands, a new complementary sequence of DNA is synthesized. The total result is formation of two new double stranded DNA sequences that are exact copies of the original double stranded DNA sequence.

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

A DNA clamp, also known as a sliding clamp, is a protein complex that serves as a processivity-promoting factor in DNA replication. As a critical component of the DNA polymerase III holoenzyme, the clamp protein binds DNA polymerase and prevents this enzyme from dissociating from the template DNA strand. The clamp-polymerase protein–protein interactions are stronger and more specific than the direct interactions between the polymerase and the template DNA strand; because one of the rate-limiting steps in the DNA synthesis reaction is the association of the polymerase with the DNA template, the presence of the sliding clamp dramatically increases the number of nucleotides that the polymerase can add to the growing strand per association event. The presence of the DNA clamp can increase the rate of DNA synthesis up to 1,000-fold compared with a nonprocessive polymerase.

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

Bacterial transcription is the process in which a segment of bacterial DNA is copied into a newly synthesized strand of messenger RNA (mRNA) with use of the enzyme RNA polymerase.

<span class="mw-page-title-main">POLD1</span> Protein-coding gene in the species Homo sapiens

DNA polymerase delta catalytic subunit(DPOD1) is an enzyme that is encoded in the human by the POLD1 gene, in the DNA polymerase delta complex. DPOD1 is responsible for synthesizing the lagging strand of DNA, and has also been implicated in some activities at the leading strand. The DPOD1 subunit encodes both DNA polymerizing and exonuclease domains, which provide the protein an important second function in proofreading to ensure replication accuracy during DNA synthesis, and in a number of types of replication-linked DNA repair following DNA damage.

RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins.

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

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">DNA polymerase alpha</span> Family of protein complexes

DNA polymerase alpha also known as Pol α is an enzyme complex found in eukaryotes that is involved in initiation of DNA replication. The DNA polymerase alpha complex consists of 4 subunits: POLA1, POLA2, PRIM1, and PRIM2.

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Further reading