Summary: DNA polymerase family A
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DNA polymerase Edit Wikipedia article
|DNA-directed DNA polymerase|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
DNA polymerase is an enzyme that synthesizes DNA molecules from deoxyribonucleotides, the building blocks of DNA. These enzymes are essential for DNA replication and usually work in pairs to create two identical DNA strands from a single original DNA molecule. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones.
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 help 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.
- 1 History
- 2 Function
- 3 Variation across species
- 3.1 Prokaryotic polymerase
- 3.2 Eukaryotic DNA polymerase
- 3.2.1 Polymerases Î², Î», Ïƒ and Î¼ (beta, lambda, sigma, and mu)
- 3.2.2 Polymerases Î±, Î´ and Îµ (alpha, delta, and epsilon)
- 3.2.3 Polymerases Î·, Î¹ and Îº (eta, iota, and kappa)
- 3.2.4 Polymerases Rev1 and Î¶ (zeta)
- 3.2.5 Telomerase
- 3.2.6 Polymerases Î³, Î¸ and Î½ (gamma, theta and nu)
- 3.2.7 Reverse transcriptase
- 4 See also
- 5 References
- 6 Further reading
- 7 External links
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. DNA polymerase II was also 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.
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.
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'â€“3' direction. No known DNA polymerase is able to begin a new chain (de novo); it can only add a nucleotide onto a pre-existing 3'-OH group, and therefore needs a primer at which it can add the first nucleotide. Primers consist of RNA or DNA bases (or both). In DNA replication, the first two bases are always RNA, and are synthesized by another enzyme called primase. Helicase and topoisomerase II are required to unwind DNA from a double-strand structure to a single-strand structure to facilitate replication of each strand consistent with the semiconservative model of DNA replication.
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'â€“5' direction, and the daughter strand is formed in a 5'â€“3' direction. This difference enables the resultant double-strand DNA formed to be composed of two DNA strands that are antiparallel to each other.
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'â€“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. 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. 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. DNA polymerization is also critical for many mutagenesis processes and is widely employed in biotechnologies.
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 in the processivity, translocation, and positioning of the DNA.
DNA polymerase's rapid catalysis is due to its processive 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.:207â€“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 Â°C, the rate was 749 nucleotides per second.
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.:207â€“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.
Variation across species
|DNA polymerase family A|
c:o6-methyl-guanine pair in the polymerase-2 basepair position
|SCOPe||1dpi / SUPFAM|
|DNA polymerase family B|
crystal structure of rb69 gp43 in complex with dna containing thymine glycol
|SCOPe||1noy / SUPFAM|
|DNA polymerase type B, organellar and viral|
phi29 dna polymerase, orthorhombic crystal form, ssdna complex
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||Types of DNA polymerase||Species||Examples||Feature|
|A||Replicative and Repair Polymerases||Eukaryotic and Prokaryotic||T7 DNA polymerase, Pol I, Pol Î³, Î¸, and Î½||Two exonuclease domains (3'-5' and 5'-3')|
|B||Replicative and Repair Polymerases||Eukaryotic and Prokaryotic||Pol II, Pol B, Pol Î¶, Pol Î±, Î´, and Îµ||3'-5 exonuclease (proofreading); viral ones use protein primer|
|C||Replicative Polymerases||Prokaryotic||Pol III||3'-5 exonuclease (proofreading)|
|D||Replicative Polymerases||Euryarchaeota||PolD (DP1/DP2 heterodimer)||No "hand" feature, RNA polymerase-like; 3'-5 exonuclease (proofreading)|
|X||Replicative and Repair Polymerases||Eukaryotic||Pol Î², Pol Ïƒ, Pol Î», Pol Î¼, and Terminal deoxynucleotidyl transferase||template-independent; 5' phosphatase (only Pol Î²)|
|Y||Replicative and Repair Polymerases||Eukaryotic and Prokaryotic||Pol Î¹, Pol Îº, Pol Î·, Pol IV, and Pol V|
|RT||Replicative and Repair Polymerases||Viruses, Retroviruses, and Eukaryotic||Telomerase, Hepatitis B virus||RNA-dependent|
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.
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'â€“5' and 5'â€“3' exonuclease activity and processing of Okazaki fragments generated during lagging strand synthesis. 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.
DNA polymerase II is a family B polymerase encoded by the polB gene. Pol II has 3'â€“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 ~200â€“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 helped stalled Pol III bypass terminal mismatches.
Pfu DNA polymerase is a heat-stable enzyme of this family found in the hyperthermophilic archaeon Pyrococcus furiosus. 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. Some viruses (including Î¦29 DNA polymerase) and mitochondrial plasmids carry polB as well.
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: Î±, the polymerase activity hub, É›, exonucleolytic proofreader, and Î¸, which may act as a stabilizer for É›. 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. The third assembly is a seven-subunit (Ï„2Î³Î´Î´â€²Ï‡Ïˆ) clamp loader complex. Recent research has classified Family C polymerases as a subcategory of Family X with no eukaryotic equivalents.[failed verification]
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. 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. In-cell fluorescent microscopy has revealed that leading strand synthesis may not be completely continuous, and Pol III* (i.e., the holoenzyme Î±, Îµ, Ï„, Î´ and Ï‡ subunits without the ÃŸ2 sliding clamp) has a high frequency of dissociation from active RFs. In these studies, the replication fork turnover rate was about 10s for Pol III*, 47s for the ÃŸ2 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. Another single-molecule study showed that DnaB helicase activity and strand elongation can proceed with decoupled, stochastic kinetics.
In E. coli, DNA polymerase IV (Pol IV) is an error-prone DNA polymerase involved in non-targeted mutagenesis. 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. 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 dinB gene have a higher rate of mutagenesis caused by DNA damaging agents.
DNA polymerase V (Pol V) is a Y-family DNA polymerase that is involved in SOS response and translesion synthesis DNA repair mechanisms. 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. In E. coli, a polymerase â€œtool beltâ€ model for switching pol III with pol IV at a stalled replication fork, where both polymerases bind simultaneously to the Î²-clamp, has been proposed. 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.
In 1998, the family D of DNA polymerase was discovered in Pyrococcus furiosus and Methanococcus jannaschii. 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 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. DP1, a Mre11-like exonuclease, is likely the precursor of small subunit of Pol Î± and Îµ, providing proofreading capabilities now lost in Eukaryotes. Its N-terminal HSH domain is similar to AAA proteins, especially Pol III subunit Î´ and RuvB, in structure. DP2 has a Class II KH domain. Pyrococcus abyssi polD is more heat-stable and more accurate than Taq polymerase, but has not yet been commercialized.
Eukaryotic DNA polymerase
Polymerases Î², Î», Ïƒ and Î¼ (beta, lambda, sigma, and mu)
Family X polymerases contain the well-known eukaryotic polymerase pol Î² (beta), as well as other eukaryotic polymerases such as Pol Ïƒ (sigma), Pol Î» (lambda), Pol Î¼ (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 Î², 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 Î» and Pol Î¼, 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.
Polymerases Î±, Î´ and Îµ (alpha, delta, and epsilon)
Pol Î± (alpha), Pol Î´ (delta), and Pol Îµ (epsilon) are members of Family B Polymerases and are the main polymerases involved with nuclear DNA replication. Pol Î± complex (pol Î±-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 Î± starts replication elongating the primer with ~20 nucleotides. Due to its high processivity, Pol Î´ takes over the leading and lagging strand synthesis from Pol Î±.:218â€“219 Pol Î´ 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 Î´ to possess processivity. Pol Îµ is encoded by the POLE1, the catalytic subunit, POLE2, and POLE3 gene. It has been reported that the function of Pol Îµ is to extend the leading strand during replication, while Pol Î´ primarily replicates the lagging strand; however, recent evidence suggested that Pol Î´ might have a role in replicating the leading strand of DNA as well. Pol Îµ's C-terminus "polymerase relic" region, despite being unnecessary for polymerase activity, 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. Pol Îµ has a larger "palm" domain that provides high processivity independently of PCNA.
Compared to other Family B polymerases, the DEDD exonuclease family responsible for proofreading is inactivated in Pol Î±. Pol Îµ 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.
Polymerases Î·, Î¹ and Îº (eta, iota, and kappa)
Pol Î· (eta), Pol Î¹ (iota), and Pol Îº (kappa), are Family Y DNA polymerases involved in the DNA repair by translesion 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 Î· is referred as XPV, because loss of this gene results in the disease Xeroderma Pigmentosum Variant. Pol Î· is particularly important for allowing accurate translesion synthesis of DNA damage resulting from ultraviolet radiation. The functionality of Pol Îº is not completely understood, but researchers have found two probable functions. Pol Îº 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.
Polymerases Rev1 and Î¶ (zeta)
Pol Î¶ 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 Î¶ 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 Î´ and Pol Îµ. These stalled polymerases activate ubiquitin complexes that in turn disassociate replication polymerases and recruit Pol Î¶ and Rev1. Together Pol Î¶ and Rev1 add deoxycytidine and Pol Î¶ extends past the lesion. Through a yet undetermined process, Pol Î¶ disassociates and replication polymerases reassociate and continue replication. Pol Î¶ 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.
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 primerâ€“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.:248â€“249
Polymerases Î³, Î¸ and Î½ (gamma, theta and nu)
Pol Î³ (gamma), Pol Î¸ (theta), and Pol Î½ (nu) are Family A polymerases. Pol Î³, encoded by the POLG gene, is the only mtDNA polymerase and therefore replicates, repairs, and has proofreading 3'â€“5' exonuclease and 5' dRP lyase activities. Any mutation that leads to limited or non-functioning Pol Î³ has a significant effect on mtDNA and is the most common cause of autosomal inherited mitochondrial disorders. Pol Î³ contains a C-terminus polymerase domain and an N-terminus 3'â€“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 Î³. Point mutation A467T in the linker region is responsible for more than one-third of all Pol Î³-associated mitochondrial disorders. While many homologs of Pol Î¸, 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 Î¸ as Family A polymerase, although the error rate for Pol Î¸ is more closely related to Family Y polymerases. Pol Î¸ 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. Pol Î½ (nu) is considered to be the least effective of the polymerase enzymes. However, DNA polymerase nu plays an active role in homology repair during cellular responses to crosslinks, fulfilling its role in a complex with helicase.
Plants use two Family A polymerases to copy both the mitochrondrial and plastid genomes. They are more similar to bacterial Pol I than they are to mamallian Pol Î³.
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.:
- Biological machines
- DNA sequencing
- Enzyme catalysis
- Genetic recombination
- Molecular cloning
- Polymerase chain reaction
- Protein domain dynamics
- Reverse transcription
- RNA polymerase
- Taq DNA polymerase
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- Maga G, Hubscher U, Spadari S, Villani G (2010). DNA Polymerases: Discovery, Characterization Functions in Cellular DNA Transactions. World Scientific Publishing Company. ISBN 978-981-4299-16-9.
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- InterPro protein view: P61875
- Makarova KS, Krupovic M, Koonin EV (2014). "Evolution of replicative DNA polymerases in archaea and their contributions to the eukaryotic replication machinery". Frontiers in Microbiology. 5: 354. doi:10.3389/fmicb.2014.00354. PMC 4104785. PMID 25101062.
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- "DNA Polymerase Families". News-medical.net. 2014-05-06. Retrieved 2014-06-28.
- Liao Y, Li Y, Schroeder JW, Simmons LA, Biteen JS (December 2016). "Single-Molecule DNA Polymerase Dynamics at a Bacterial Replisome in Live Cells". Biophysical Journal. 111 (12): 2562â€“2569. Bibcode:2016BpJ...111.2562L. doi:10.1016/j.bpj.2016.11.006. PMC 5192695. PMID 28002733.
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- Goodman MF (2002). "Error-prone repair DNA polymerases in prokaryotes and eukaryotes". Annual Review of Biochemistry. 71: 17â€“50. doi:10.1146/annurev.biochem.71.083101.124707. PMID 12045089.
- Mori T, Nakamura T, Okazaki N, Furukohri A, Maki H, Akiyama MT (2012). "Escherichia coli DinB inhibits replication fork progression without significantly inducing the SOS response". Genes & Genetic Systems. 87 (2): 75â€“87. doi:10.1266/ggs.87.75. PMID 22820381.
- Jarosz DF, Godoy VG, Walker GC (April 2007). "Proficient and accurate bypass of persistent DNA lesions by DinB DNA polymerases". Cell Cycle. 6 (7): 817â€“22. doi:10.4161/cc.6.7.4065. PMID 17377496.
- Patel M, Jiang Q, Woodgate R, Cox MM, Goodman MF (June 2010). "A new model for SOS-induced mutagenesis: how RecA protein activates DNA polymerase V". Critical Reviews in Biochemistry and Molecular Biology. 45 (3): 171â€“84. doi:10.3109/10409238.2010.480968. PMC 2874081. PMID 20441441.
- Sutton MD, Walker GC (July 2001). "Managing DNA polymerases: coordinating DNA replication, DNA repair, and DNA recombination". Proceedings of the National Academy of Sciences of the United States of America. 98 (15): 8342â€“9. Bibcode:2001PNAS...98.8342S. doi:10.1073/pnas.111036998. PMC 37441. PMID 11459973.
- Raychaudhury P, Basu AK (March 2011). "Genetic requirement for mutagenesis of the G[8,5-Me]T cross-link in Escherichia coli: DNA polymerases IV and V compete for error-prone bypass". Biochemistry. 50 (12): 2330â€“8. doi:10.1021/bi102064z. PMC 3062377. PMID 21302943.
- Ishino Y, Komori K, Cann IK, Koga Y (April 1998). "A novel DNA polymerase family found in Archaea". Journal of Bacteriology. 180 (8): 2232â€“6. PMC 107154. PMID 9555910.
- Sauguet L, Raia P, Henneke G, Delarue M (2016). "Shared active site architecture between archaeal PolD and multi-subunit RNA polymerases revealed by X-ray crystallography". Nature Communications. 7: 12227. Bibcode:2016NatCo...712227S. doi:10.1038/ncomms12227. PMC 4996933. PMID 27548043.
- Yamasaki K, Urushibata Y, Yamasaki T, Arisaka F, Matsui I (August 2010). "Solution structure of the N-terminal domain of the archaeal D-family DNA polymerase small subunit reveals evolutionary relationship to eukaryotic B-family polymerases". FEBS Letters. 584 (15): 3370â€“5. doi:10.1016/j.febslet.2010.06.026. PMID 20598295.
- Ishino S, Ishino Y (2014). "DNA polymerases as useful reagents for biotechnology - the history of developmental research in the field". Frontiers in Microbiology. 5: 465. doi:10.3389/fmicb.2014.00465. PMC 4148896. PMID 25221550.
- Yamtich J, Sweasy JB (May 2010). "DNA polymerase family X: function, structure, and cellular roles". Biochimica et Biophysica Acta. 1804 (5): 1136â€“50. doi:10.1016/j.bbapap.2009.07.008. PMC 2846199. PMID 19631767.
- Chansky ML, Marks A, Peet A (2012). Marks' Basic Medical Biochemistry: a clinical approach (4th ed.). Philadelphia: Wolter Kluwer Health/Lippincott Williams & Wilkins. p. chapter13. ISBN 978-1608315727.
- Chung DW, Zhang JA, Tan CK, Davie EW, So AG, Downey KM (December 1991). "Primary structure of the catalytic subunit of human DNA polymerase delta and chromosomal location of the gene". Proceedings of the National Academy of Sciences of the United States of America. 88 (24): 11197â€“201. Bibcode:1991PNAS...8811197C. doi:10.1073/pnas.88.24.11197. PMC 53101. PMID 1722322.
- Pursell ZF, Isoz I, LundstrÃ¶m EB, Johansson E, Kunkel TA (July 2007). "Yeast DNA polymerase epsilon participates in leading-strand DNA replication". Science. 317 (5834): 127â€“30. Bibcode:2007Sci...317..127P. doi:10.1126/science.1144067. PMC 2233713. PMID 17615360.
- Lujan SA, Williams JS, Kunkel TA (September 2016). "DNA Polymerases Divide the Labor of Genome Replication". Trends in Cell Biology. 26 (9): 640â€“654. doi:10.1016/j.tcb.2016.04.012. PMC 4993630. PMID 27262731.
- Johnson RE, Klassen R, Prakash L, Prakash S (July 2015). "A Major Role of DNA Polymerase Î´ in Replication of Both the Leading and Lagging DNA Strands". Molecular Cell. 59 (2): 163â€“175. doi:10.1016/j.molcel.2015.05.038. PMC 4517859. PMID 26145172.
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|Wikimedia Commons has media related to DNA polymerases.|
- DNA+polymerases at the US National Library of Medicine Medical Subject Headings (MeSH)
- PDB Molecule of the Month DNA polymerase
- Unusual repair mechanism in DNA polymerase lambda, Ohio State University, July 25, 2006.
- A great animation of DNA Polymerase from WEHI at 1:45 minutes in
- 3D macromolecular structures of DNA polymerase from the EM Data Bank(EMDB)
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
DNA polymerase family A Provide feedback
No Pfam abstract.
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001098
Synonym(s): DNA nucleotidyltransferase (DNA-directed)
DNA-directed DNA polymerases( EC ) are the key enzymes catalysing the accurate replication of DNA. They require either a small RNA molecule or a protein as a primer for the de novo synthesis of a DNA chain. A number of polymerases belong to this family [ PUBMED:2196557 , PUBMED:1870963 , PUBMED:8451181 ].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||DNA-directed DNA polymerase activity (GO:0003887)|
|DNA binding (GO:0003677)|
|Biological process||DNA replication (GO:0006260)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Author:||Sonnhammer ELL , Griffiths-Jones SR|
|Number in seed:||659|
|Number in full:||13855|
|Average length of the domain:||364.70 aa|
|Average identity of full alignment:||30 %|
|Average coverage of the sequence by the domain:||40.10 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||22|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the DNA_pol_A domain has been found. There are 280 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
Loading structure mapping...
AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.