- Open Access
Evolution of DNA polymerases: an inactivated polymerase-exonuclease module in Pol ε and a chimeric origin of eukaryotic polymerases from two classes of archaeal ancestors
© Tahirov et al; licensee BioMed Central Ltd. 2009
- Received: 16 March 2009
- Accepted: 18 March 2009
- Published: 18 March 2009
Evolution of DNA polymerases, the key enzymes of DNA replication and repair, is central to any reconstruction of the history of cellular life. However, the details of the evolutionary relationships between DNA polymerases of archaea and eukaryotes remain unresolved.
We performed a comparative analysis of archaeal, eukaryotic, and bacterial B-family DNA polymerases, which are the main replicative polymerases in archaea and eukaryotes, combined with an analysis of domain architectures. Surprisingly, we found that eukaryotic Polymerase ε consists of two tandem exonuclease-polymerase modules, the active N-terminal module and a C-terminal module in which both enzymatic domains are inactivated. The two modules are only distantly related to each other, an observation that suggests the possibility that Pol ε evolved as a result of insertion and subsequent inactivation of a distinct polymerase, possibly, of bacterial descent, upstream of the C-terminal Zn-fingers, rather than by tandem duplication. The presence of an inactivated exonuclease-polymerase module in Pol ε parallels a similar inactivation of both enzymatic domains in a distinct family of archaeal B-family polymerases. The results of phylogenetic analysis indicate that eukaryotic B-family polymerases, most likely, originate from two distantly related archaeal B-family polymerases, one form giving rise to Pol ε, and the other one to the common ancestor of Pol α, Pol δ, and Pol ζ. The C-terminal Zn-fingers that are present in all eukaryotic B-family polymerases, unexpectedly, are homologous to the Zn-finger of archaeal D-family DNA polymerases that are otherwise unrelated to the B family. The Zn-finger of Polε shows a markedly greater similarity to the counterpart in archaeal PolD than the Zn-fingers of other eukaryotic B-family polymerases.
Evolution of eukaryotic DNA polymerases seems to have involved previously unnoticed complex events. We hypothesize that the archaeal ancestor of eukaryotes encoded three DNA polymerases, namely, two distinct B-family polymerases and a D-family polymerase all of which contributed to the evolution of the eukaryotic replication machinery. The Zn-finger might have been acquired from PolD by the B-family form that gave rise to Pol ε prior to or in the course of eukaryogenesis, and subsequently, was captured by the ancestor of the other B-family eukaryotic polymerases. The inactivated polymerase-exonuclease module of Pol ε might have evolved by fusion with a distinct polymerase, rather than by duplication of the active module of Pol ε, and is likely to play an important role in the assembly of eukaryotic replication and repair complexes.
This article was reviewed by Patrick Forterre, Arcady Mushegian, and Chris Ponting. For the full reviews, please go to the Reviewers' Reports section.
- Author Response
- Phyre Server
- Family Polymerase
- Archaeal Ancestor
- Modern Eukaryote
DNA-dependent DNA polymerases (DdDps) are essential components of all cellular life forms inasmuch as genomes of all modern cells consist of DNA whose replication requires the activity of one or more DdDps [1, 2]. Most of the DNA viruses with relatively large genomes also encode their own DdDps . The great majority of cellular organisms possess several DdDps that operate during DNA chain elongation during replication and/or in diverse repair processes [4, 5].
Structural and inferred evolutionary relationships between DdDps comprise a complex network. There are several families of DdDps that are only distantly related or unrelated to each other . The replicative polymerases are sharply divided between the bacterial and archaeal-eukaryotic types that appear not to be homologous [7, 8]. In bacteria, replication is performed by C-family polymerases that are not found in archaea or eukaryotes, whereas all archaea and eukaryotes, as well as a huge diversity of viruses, encode B-family polymerases that are responsible for genome replication in all eukaryotes and some of the archaea [6, 9]. All eukaryotes, in particular, possess four paralogous B-family polymerases denoted Pol α, Pol δ, Pol ε, and Pol ζ involved in DNA replication and repair [5, 10]. Of these, Pol α and Pol δ are essential components of the DNA replication machinery; Pol ε has an apparent role in replication, but its exact function is less clear, whereas Polζ is involved in translesion DNA synthesis [11–17]. Euryarchaeota, in addition, possess a distinct D family polymerase that seems to make a substantial contribution to replication (the replication of archaeal DNA is not understood in as much detail as bacterial or eukaryotic replication) and is unrelated to both B and C family polymerases [18–20]. Recently, PolD was detected also in the putative phyla Nanoarchaeota , Thaumarchaeota (formerly mesophilic Crenarchaeota) , and Korarchaeota , suggesting the possibility that this DdDp is ancestral in archaea.
Here we report results of comparisons of protein sequences of eukaryotic and archaeal DdDps that reveal unexpected aspects of their domain architectures and evolution, and lead to specific functional implications.
Inactivated polymerase and exonuclease domains in the C-terminal portion of Pol ε
Pol ε, one of the paralogous B family polymerases that are conserved in all eukaryotes, is a very large protein that typically consists of 2000 or more amino acid residues . The functionally characterized proofreading 3'-5' exonuclease (Exo) and polymerase (Pol) domains are located in the N-terminal half of this protein whereas the C-terminal half contains no experimentally characterized or readily detectable domains except for two Zn-finger modules at the end of the sequence [11, 17, 24–26]. The Pol ε holoenzyme heterotetramer , the 20 Å resolution structure of which has been determined by cryo-electron microscopy (cryo-EM) , contains, in addition to the large catalytic subunit, three smaller subunits, DPB2-4; the DPB2 subunit is essential for viability, and its proper structure is required for high fidelity of genome replication . Site-directed mutagenesis experiments demonstrated that the Zn-fingers of Pol ε are required for its interaction with DPB2 . Deletion of the other two accessory subunits is not lethal but leads to elevated mutation rates [30, 31].
The sequences of the Zn fingers in Pol α, Pol δ and Pol ζ are adjacent to the C-terminal portion of the catalytic domain that is homologous to the sequences of the Thumb subdomain in the available crystal structures of B-family DdDps. By contrast, the Zn fingers in Pol ε are separated from the N-terminal catalytic domains by a large insert that is similar in size to the N-terminal Exo-Pol module. Examination of the Cryo-EM structure  indicates that this insert and the DPB2-binding subdomain (Zn fingers) are, largely, structured and bound to each other; furthermore, the presence of this insert places the DPB2-binding area spatially apart from the N-terminal, catalytic Exo-Pol module. Somewhat paradoxically, it was shown by deletion mutagenesis and site-directed mutagenesis that the N-terminal, catalytic portion of Pol ε is not required for viability whereas the uncharacterized C-terminal portion is essential [11, 16, 24–26].
We employed secondary structure prediction and fold recognition in combination with different sequence similarity search strategies in an attempt to elucidate the origin and possible functions of the essential C-terminal region of Polε. Secondary structure prediction and automated three-dimensional model building for the N-terminal 1200 amino acids of human Pol ε using the Phyre server , as expected, revealed a typical DNA polymerase fold (pdb: 1wn7, 1d5a, 1s5j, 1q8i, 2gv9, 2p5o) with a 100% confidence. Strikingly, the search with the remaining amino acids 1201–2286 of human Pol ε also revealed a DNA polymerase fold for the sequences preceding the Zn fingers with the confidence of 95% (E. coli DNA polymerase II, PDB code 1q8i), 90% (Desulfurococcus sp. tok DNA Polymerase, 1d5a) and 85% (Thermococcus kodakaraensis family B DNA polymerase, 1wn7). Although we did expect to detect some Thumb subdomain-like fold that would stabilize the positions of Zn fingers, the discovery of the entire second polymerase and exonuclease module was highly surprising. This unexpected finding prompted us to initiate a further, in-depth sequence analysis in an attempt to elucidate the origin and possible functions of the essential C-terminal region of Pol ε.
A PSI-BLAST search  with the C-terminal portion of the Pol ε sequence from Saccharomyces cerevisiae (amino acid positions from 1170 to 2085 aa) used as the query (with E = 0.001 inclusion threshold and composition based statistics on) reveals similarity to the sequence of DNA polymerase II of Photobacterium profundum (GI:90410522) of the B-family at the 3rd iteration, with E-value = 2e-05; numerous sequences of B-family polymerases were detected in subsequent iterations. The same sequence was used as a query for an HHpred search . This method detects the similarity with a B-family polymerase from the archaeon Thermococcus sp. (pdb: 1qht) with E-value = 4.9e-06 as the second top hit (the first one is a self-hit to pfam08490: DUF1744, Domain of unknown function) and several additional hits to different sequences and profiles of B-family polymerases with statistically significant E-values.
Unexpected evolutionary affinities of the Zn-finger modules of eukaryotic B family DNA polymerases
Origin of eukaryotic B-family DNA polymerases
The subsequent events in the evolution of eukaryotic B-family DdDps that occurred prior to the radiation of the major lineages of eukaryotes included not only two duplications of the Pol-Exo block that led to the origin of polymerases α,δ, and ζ, but also the duplication of the Zn-finger, probably, in the ancestral Polε, with the subsequent acquisition of the two-finger module by the common ancestor of Polα, Polδ, and Polζ. The inactivated C-terminal portion of the Polε is more likely to result from a fusion of two distantly related B-family polymerases as opposed to the intragenic duplication scenario. The topology of the phylogenetic tree suggests that the source of the C-terminal portion of Pol ε could be a proteobacterial (or bacteriophage) B-family polymerase (Figure 4) although, given the long Pol ε branch, its origin cannot be determined with any confidence. In principle, a long-branch artifact could even obscure a duplication of the N-terminal portion of Pol ε; however, this seems unlikely considering that the N-terminal sequence shows a distinct pattern of indels as opposed to a common pattern in the C-terminal sequence and the rest of the eukaryotic B-family polymerases (Figure 2).
The analysis described here reveals the complexity of the evolution of only one, although biologically central, group of eukaryotic proteins, the B-family DNA polymerases involved in genome replication and some repair processes. Evolution of the eukaryotic B-family polymerases seems to have involved several previously unnoticed events. At face value, eukaryotic B-family DdDps appear to be chimeric with respect to their archaeal ancestors, with the catalytic portion (Pol and Exo domains along with the N-terminal uracil-binding domain ) derived from archaeal B-family polymerases and the Zn-finger derived from PolD (Figure 5). The derivation of the small subunits of eukaryotic B-family polymerases, such as DPB2, from the exonuclease subunits of the archaeal PolD further emphasizes the joint contributions of the B-family and D-family archaeal polymerases to the evolution of the eukaryotic replication machinery. It is unclear, however, at what stage of evolution the chimeric polymerases evolved. The possibility remains that this fusion of domains that, in archaea, so far have been detected separately, is characteristic of the hypothetical (extinct or extant but not yet discovered) deep lineage of archaea that provided the archaeal heritage of eukaryotes .
The unexpected observation that triggered this analysis is the presence, in the C-terminal regions of the large, catalytic subunits of all eukaryotic Polε, of apparently inactivated versions of the Exo and Pol domains. These sequences are conserved in all eukaryotes and, notably, have been identified as essential by deletion mutagenesis [11, 25, 26]. Thus, it appears certain that, despite the inactivation of both catalytic activities, the C-terminal portion of Pol ε plays a key role in DNA replication of all eukaryotes, conceivably, as a structural component that is indispensable for the assembly of replication complexes at the origins , with likely additional functions in repair and cell cycle regulation . Inactivation of enzymatic activities of polymerase subunits is becoming a rather general theme in the evolution of the architecture of the replication machinery, two other cases being the inactivation of the nuclease domain in the small subunits of eukaryotic B-family polymerases [36, 40, 49], and the inactivation of both catalytic domains in a distinct family of archaeal polymerase homologs . Strikingly, the evolution of Pol ε seems to have involved a concerted inactivation of both the Exo and Pol domains of a B-family polymerase (possibly, one that fused with the ancestral B-family polymerase) and of the exonuclease subunit of PolD, suggesting that selective pressure exists for the utilization of these inactivated derivatives of replicative enzymes as structural components of replicative complexes.
Another case of functional inactivation despite structural conservation is the uracil recognition domain that is conserved in archaeal and eukaryotic B-family polymerases (Fig 4) but lost the capacity to sense uracil in front of the moving polymerase in eukaryotes . Mechanistic characterization of the inactivated polymerase subunits and domains is expected to shed new light on the functions of the replication apparatus.
On a more general note, the present analysis indicates that footprints of undetected evolutionary events with important functional implications are still lurking in even supposedly well-characterized proteins. Conceivably, a variety of non-trivial evolutionary connections between eukaryotic proteins and their prokaryotic ancestors remain to be discovered, leading to unusual evolutionary scenarios.
All analyzed sequence were from the NCBI's RefSeq database . Multiple alignments of protein sequences were constructed by combining the results obtained with the PROMALS program  and the MUSCLE program , followed by a minimal manual correction on the basis of local alignments obtained using PSI-BLAST (see Additional File 1). Protein sequence motifs were represented using sequence LOGOs where the height of the amino acid symbols is a function of the frequency of the given amino acid in the given position [54, 55]. Protein secondary structure was predicted using the PSIPRED program . Protein fold recognition was performed using the Phyre server .
Maximum likelihood (ML) phylogenetic trees were constructed from the alignment of the most conserved positions of the Pol and Exo domains of the B-family polymerases (279 positions altogether, with only a few gaps within the conserved blocks) by using the MOLPHY program [57, 58] with the JTT substitution matrix to perform local rearrangement of an original Fitch tree . The MOLPHY program was also used to compute RELL bootstrap values. The topology of the tree was validated using independent ML methods implemented in the Treefinder  and RaxML  programs with optimized JTT, WAG and RtRev substitution matrices (see Additional File 2).
Reviewer 1: Patrick Forterre, Institut Pasteur
The paper by Tahirov and colleagues reports a very exciting observation: they have shown convincingly, using a combination of in silico approaches based on structural comparison and iterative Psi-BLAST analyses, that the C terminal domain of the eukaryotic DNA polymerase ε, corresponds to an inactivated DNA polymerase of the B family. The eukaryotic DNA polymerase ε thus appears to be formed by the fusion of an active DNA polymerase B (in N-terminal) and an inactive DNA polymerase B (in C-terminal). Amazingly, the inactive DNA polymerase B does not seem to have originated from a duplication of the active one, but by the fusion of a bacterial-like DNA polymerase B (such as E. coli DNA polymerase II). This is a very interesting observation that deserves publication. The authors also notice that the two Zinc fingers of the eukaryotic DNA polymerase ε are more related to Zinc fingers of archaeal DNA polymerases D than to those of other DNA polymerases B. This is in line with the fact that archaeal DNA polymerases D and eukaryotic DNA polymerases ε both interact with homologous subunits in Archaea and Eukarya. From these two observations, the authors speculate about the origin and evolution of eukaryotic DNA polymerases. I think that the authors should more clearly distinguish between their observations and evolutionary hypotheses. For instance, in the abstract, the hypotheses are described in the "result section" and even introduce this section as if they were bona fide results. The main and exciting result is only presented as an additional observation!!! "In addition, we found that.....". I think that the hypothesis favoured by the author should be mentioned only in the conclusion.
Authors response: We appreciate these constructive suggestions and have revised the Abstract accordingly. In the main text, the description of the inactivated module of Pol ε already preceded the rest of the analysis, so no change was necessary.
Ideally, the authors should have discussed their observations in the context of alternative hypotheses on the origin of eukaryotes and the eukaryotic DNA replication apparatus (see below). In my opinion, in discussing evolutionary scenarios, terms such as "archaeal ancestor" (already in the title and abstract conclusions) (see Figure also 5) should be avoided. The term archaeal ancestor is confusing since the common ancestor of Archaea and proto-eukaryotes was probably neither a proto-eukaryote nor an archaeon. Similarly, the Human does not descend from Apes, but Apes and Human have a common ancestor.
Authors response: This point is often brought up, and a reminder, we hope, will be helpful to the reader. It is true that Homo sapiens did not evolve from Pan troglodytes or any other living great ape species but rather shares a common ancestor with them. However, that common ancestor was, necessarily, an ape (distinct from any extant ape, of course), so the phrase "ape ancestor of humans" is not confusing, in our opinion. Ditto regarding "archaeal ancestor of eukaryotes".
From our own analysis of the evolution of the DNA replication apparatus (unpublished), it is indeed likely that the last common ancestor of Archaea had two DNA polymerases of the B family and one of the D family (as suggested in Figure 5A) and this was possibly also the case for the last common ancestor of Archaea and proto-eucaryotes (as suggested by the authors). The authors imagine a scenario of evolution going from this "simple" ancestor to modern eukaryotes (transformation of the two ancestral polymerases B in four polymerases B and loss of the polymerase D in the lineage of modern eukaryotes). However, one cannot exclude other scenarios, such as the presence of more than two polymerases B in the common ancestor of archaea and proto-eucaryotes (with loss of DNA polymerase D in Archaea and of some DNA polymerase B in Archaea), and/or introduction of DNA polymerases of viral origin in Archaea and/or in the lineage of proto-eucaryotes . Since viral DNA polymerases of the B family are intermixed with cellular DNA polymerases in phylogenetioc tree [63, 64], it should be in any case interesting to extend the present analysis to viral DNA polymerases as well.
Authors response: We agree that alternative scenarios are imaginable. They might somewhat less parsimonious but parsimony is at best a rough guide in the study of such complex evolutionary scenarios. Analysis of viral polymerases is interesting although it is complicated by the typical high rate of evolution of viral proteins, even essential ones.
Reviewer 2: Arcady Mushegian, Stowers Institute
Abstract: "of archaeal, eukaryotic, and bacterial B-family DNA polymerases, the main replicative polymerases in archaea and eukaryotes" is awkward.
Ibid. "eukaryotic B-family polymerases, most likely, originate from two distinct archaeal ancestors" – perhaps change to "there are two subgroups of eukaryotic B-family polymerases, each most likely originating from its own archaeal B-family ancestor". Otherwise. "two distinct archaeal ancestors" can be mistaken for the description of B+D chimera in the following sentence.
"As proposed previously, inactivated polymerase subunits are likely to perform essential functions in the assembly of replicative complexes" (also Conclusions) – a bolder suggestion may be that these proteins still facilitate a subset of catalytic reactions, if the maintainance of a proper conformation of subsrates/ligands is sufficient for catalysis – processive synthesis may not work well that way, but perhaps some sort of proofreading or ejection of abortive products might – discuss?
Evolutionary scenario and Fig. 5: Why proteobacterial-type PolB, the source of the C-terminal domain tandem in eukaryotic Pol epsilon, has to be the symbiogenetic/mitochondrial acquisition – can it be a phage contribution instead?
Authors' response: in principle, it could be a phage contribution but we do not see any specific indications of such an origin of the inactivated polymerase module of Pol ε.
Reviewer 3: Chris Ponting, Oxford University
This manuscript reports the identification of a tandem exonuclease-polymerase homology module within the C-terminal regions of DNA polymerase epsilons. The authors propose these domains arose by gene fusion rather than intra-gene duplication and that they dispensed with their enzymatic activities. Also discussed are the evolutionary implications of similarities between zinc fingers of DNA polymerase epsilon and archaeal PolD.
This is a well-written and compelling report that contributes significantly to our understanding of the evolution of cellular DNA replication and repair. The sequence similarity methods and the statistical analyses used are entirely appropriate. These findings should now re-focus attention on the molecular mechanisms of these apparently inactivated domains in Pol-epsilon.
Authors' response: We appreciate these constructive comments and cannot agree more with regard to the importance of experimental investigation of the functions and mechanisms of the inactivated module of Pol ε. Moreover, such experiments are currently underway in the laboratory of one of us (YIP) at the University of Nebraska Medical Center.
KSM, IBR, and EVK are supported by intramural funds of the DHHS (NIH, National Library of Medicine). YIP was supported in part by NCI grant R01 CA129925-01A2, an Eppley Institute Pilot grant and NE DHHS 2008 grant LB506. THT is supported by the Eppley Institute Pilot grant and in part by NIGMS grant 1R01GM082923-01A2.
- Kornberg A, Baker T: DNA Replication. 1992, New York, NY: W. H. Freeman and Co, 2Google Scholar
- Johnson A, O'Donnell M: Cellular DNA replicases: components and dynamics at the replication fork. Annu Rev Biochem. 2005, 74: 283-315.PubMedView ArticleGoogle Scholar
- Iyer LM, Balaji S, Koonin EV, Aravind L: Evolutionary genomics of nucleo-cytoplasmic large DNA viruses. Virus Res. 2006, 117: 156-184.PubMedView ArticleGoogle Scholar
- Goodman MF, Tippin B: The expanding polymerase universe. Nat Rev Mol Cell Biol. 2000, 1: 101-109.PubMedView ArticleGoogle Scholar
- Pavlov YI, Shcherbakova PV, Rogozin IB: Roles of DNA polymerases in replication, repair, and recombination in eukaryotes. Int Rev Cytol. 2006, 255: 41-132.PubMedView ArticleGoogle Scholar
- Burgers PM, Koonin EV, Bruford E, Blanco L, Burtis KC, Christman MF, Copeland WC, Friedberg EC, Hanaoka F, Hinkle DC, et al: Eukaryotic DNA polymerases: proposal for a revised nomenclature. J Biol Chem. 2001, 276: 43487-43490.PubMedView ArticleGoogle Scholar
- Leipe DD, Aravind L, Koonin EV: Did DNA replication evolve twice independently?. Nucleic Acids Res. 1999, 27: 3389-3401.PubMedPubMed CentralView ArticleGoogle Scholar
- Bailey S, Wing RA, Steitz TA: The structure of T. aquaticus DNA polymerase III is distinct from eukaryotic replicative DNA polymerases. Cell. 2006, 126: 893-904.PubMedView ArticleGoogle Scholar
- Grabowski B, Kelman Z: Archeal DNA replication: eukaryal proteins in a bacterial context. Annu Rev Microbiol. 2003, 57: 487-516.PubMedView ArticleGoogle Scholar
- Hubscher U, Maga G, Spadari S: Eukaryotic DNA polymerases. Annu Rev Biochem. 2002, 71: 133-163.PubMedView ArticleGoogle Scholar
- Kesti T, Flick K, Keranen S, Syvaoja JE, Wittenberg C: DNA polymerase epsilon catalytic domains are dispensable for DNA replication, DNA repair, and cell viability. Mol Cell. 1999, 3: 679-685.PubMedView ArticleGoogle Scholar
- Waga S, Masuda T, Takisawa H, Sugino A: DNA polymerase epsilon is required for coordinated and efficient chromosomal DNA replication in Xenopus egg extracts. Proc Natl Acad Sci USA. 2001, 98: 4978-4983.PubMedPubMed CentralView ArticleGoogle Scholar
- Rytkonen AK, Vaara M, Nethanel T, Kaufmann G, Sormunen R, Laara E, Nasheuer HP, Rahmeh A, Lee MY, Syvaoja JE, Pospiech H: Distinctive activities of DNA polymerases during human DNA replication. Febs J. 2006, 273: 2984-3001.PubMedView ArticleGoogle Scholar
- Burgers PM: Polymerase dynamics at the eukaryotic DNA replication fork. J Biol Chem. 2009, 284: 4041-5.PubMedPubMed CentralView ArticleGoogle Scholar
- Kunkel TA, Burgers PM: Dividing the workload at a eukaryotic replication fork. Trends Cell Biol. 2008, 18: 521-527.PubMedPubMed CentralView ArticleGoogle Scholar
- Pospiech H, Syvaoja JE: DNA polymerase epsilon – more than a polymerase. ScientificWorldJournal. 2003, 3: 87-104.PubMedView ArticleGoogle Scholar
- Pursell ZF, Kunkel TA: DNA polymerase epsilon: a polymerase of unusual size (and complexity). Prog Nucleic Acid Res Mol Biol. 2008, 82: 101-145.PubMedPubMed CentralView ArticleGoogle Scholar
- Ishino Y, Ishino S: DNA polymerases from euryarchaeota. Methods Enzymol. 2001, 334: 249-260.PubMedView ArticleGoogle Scholar
- Ishino Y, Komori K, Cann IK, Koga Y: A novel DNA polymerase family found in Archaea. J Bacteriol. 1998, 180: 2232-2236.PubMedPubMed CentralGoogle Scholar
- Henneke G, Flament D, Hubscher U, Querellou J, Raffin JP: The hyperthermophilic euryarchaeota Pyrococcus abyssi likely requires the two DNA polymerases D and B for DNA replication. J Mol Biol. 2005, 350: 53-64.PubMedView ArticleGoogle Scholar
- Waters E, Hohn MJ, Ahel I, Graham DE, Adams MD, Barnstead M, Beeson KY, Bibbs L, Bolanos R, Keller M, et al: The genome of Nanoarchaeum equitans: insights into early archaeal evolution and derived parasitism. Proc Natl Acad Sci USA. 2003, 100: 12984-12988.PubMedPubMed CentralView ArticleGoogle Scholar
- Brochier-Armanet C, Boussau B, Gribaldo S, Forterre P: Mesophilic Crenarchaeota: proposal for a third archaeal phylum, the Thaumarchaeota. Nat Rev Microbiol. 2008, 6: 245-252.PubMedView ArticleGoogle Scholar
- Elkins JG, Podar M, Graham DE, Makarova KS, Wolf Y, Randau L, Hedlund BP, Brochier C, Kunin V, Anderson I, et al: A korarchaeal genome reveals new insights into the evolution of the Archaea. Proc Natl Acad Sci USA. 2008Google Scholar
- Dua R, Levy DL, Campbell JL: Role of the putative zinc finger domain of Saccharomyces cerevisiae DNA polymerase epsilon in DNA replication and the S/M checkpoint pathway. J Biol Chem. 1998, 273: 30046-30055.PubMedView ArticleGoogle Scholar
- Feng W, D'Urso G: Schizosaccharomyces pombe cells lacking the amino-terminal catalytic domains of DNA polymerase epsilon are viable but require the DNA damage checkpoint control. Mol Cell Biol. 2001, 21: 4495-4504.PubMedPubMed CentralView ArticleGoogle Scholar
- Dua R, Levy DL, Campbell JL: Analysis of the essential functions of the C-terminal protein/protein interaction domain of Saccharomyces cerevisiae pol epsilon and its unexpected ability to support growth in the absence of the DNA polymerase domain. J Biol Chem. 1999, 274: 22283-22288.PubMedView ArticleGoogle Scholar
- Chilkova O, Jonsson BH, Johansson E: The quaternary structure of DNA polymerase epsilon from Saccharomyces cerevisiae. J Biol Chem. 2003, 278: 14082-14086.PubMedView ArticleGoogle Scholar
- Asturias FJ, Cheung IK, Sabouri N, Chilkova O, Wepplo D, Johansson E: Structure of Saccharomyces cerevisiae DNA polymerase epsilon by cryo-electron microscopy. Nat Struct Mol Biol. 2006, 13: 35-43.PubMedView ArticleGoogle Scholar
- Jaszczur M, Flis K, Rudzka J, Kraszewska J, Budd ME, Polaczek P, Campbell JL, Jonczyk P, Fijalkowska IJ: Dpb2p, a noncatalytic subunit of DNA polymerase epsilon, contributes to the fidelity of DNA replication in Saccharomyces cerevisiae. Genetics. 2008, 178: 633-647.PubMedPubMed CentralView ArticleGoogle Scholar
- Araki H, Hamatake RK, Morrison A, Johnson AL, Johnston LH, Sugino A: Cloning DPB3, the gene encoding the third subunit of DNA polymerase II of Saccharomyces cerevisiae. Nucleic Acids Res. 1991, 19: 4867-4872.PubMedPubMed CentralView ArticleGoogle Scholar
- Northam MR, Garg P, Baitin DM, Burgers PM, Shcherbakova PV: A novel function of DNA polymerase zeta regulated by PCNA. Embo J. 2006, 25: 4316-4325.PubMedPubMed CentralView ArticleGoogle Scholar
- Bennett-Lovsey RM, Herbert AD, Sternberg MJ, Kelley LA: Exploring the extremes of sequence/structure space with ensemble fold recognition in the program Phyre. Proteins. 2008, 70: 611-625.PubMedView ArticleGoogle Scholar
- Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997, 25: 3389-3402.PubMedPubMed CentralView ArticleGoogle Scholar
- Soding J, Biegert A, Lupas AN: The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res. 2005, 33: W244-248.PubMedPubMed CentralView ArticleGoogle Scholar
- Rogozin IB, Makarova KS, Pavlov YI, Koonin EV: A highly conserved family of inactivated archaeal B family DNA polymerases. Biol Direct. 2008, 3: 32-PubMedPubMed CentralView ArticleGoogle Scholar
- Aravind L, Koonin EV: Phosphoesterase domains associated with DNA polymerases of diverse origins. Nucleic Acids Res. 1998, 26: 3746-3752.PubMedPubMed CentralView ArticleGoogle Scholar
- Cann IK, Komori K, Toh H, Kanai S, Ishino Y: A heterodimeric DNA polymerase: evidence that members of Euryarchaeota possess a distinct DNA polymerase. Proc Natl Acad Sci USA. 1998, 95: 14250-14255.PubMedPubMed CentralView ArticleGoogle Scholar
- Shen Y, Tang XF, Matsui E, Matsui I: Subunit interaction and regulation of activity through terminal domains of the family D DNA polymerase from Pyrococcus horikoshii. Biochem Soc Trans. 2004, 32: 245-249.PubMedView ArticleGoogle Scholar
- Jokela M, Eskelinen A, Pospiech H, Rouvinen J, Syvaoja JE: Characterization of the 3' exonuclease subunit DP1 of Methanococcus jannaschii replicative DNA polymerase D. Nucleic Acids Res. 2004, 32: 2430-2440.PubMedPubMed CentralView ArticleGoogle Scholar
- Makiniemi M, Pospiech H, Kilpelainen S, Jokela M, Vihinen M, Syvaoja JE: A novel family of DNA-polymerase-associated B subunits. Trends Biochem Sci. 1999, 24: 14-16.PubMedView ArticleGoogle Scholar
- Braithwaite DK, Ito J: Compilation, alignment, and phylogenetic relationships of DNA polymerases. Nucleic Acids Res. 1993, 21: 787-802.PubMedPubMed CentralView ArticleGoogle Scholar
- Filee J, Forterre P, Sen-Lin T, Laurent J: Evolution of DNA polymerase families: evidences for multiple gene exchange between cellular and viral proteins. J Mol Evol. 2002, 54: 763-773.PubMedView ArticleGoogle Scholar
- Edgell DR, Malik SB, Doolittle WF: Evidence of independent gene duplications during the evolution of archaeal and eukaryotic family B DNA polymerases. Mol Biol Evol. 1998, 15: 1207-1217.PubMedView ArticleGoogle Scholar
- Iwai T, Kurosawa N, Itoh YH, Kimura N, Horiuchi T: Sequence analysis of three family B DNA polymerases from the thermoacidophilic crenarchaeon Sulfurisphaera ohwakuensis. DNA Res. 2000, 7: 243-251.PubMedView ArticleGoogle Scholar
- Makarova KS, Wolf YI, Mekhedov SL, Mirkin BG, Koonin EV: Ancestral paralogs and pseudoparalogs and their role in the emergence of the eukaryotic cell. Nucleic Acids Res. 2005, 33: 4626-4638.PubMedPubMed CentralView ArticleGoogle Scholar
- Yutin N, Makarova KS, Mekhedov SL, Wolf YI, Koonin EV: The deep archaeal roots of eukaryotes. Mol Biol Evol. 2008, 25: 1619-1630.PubMedPubMed CentralView ArticleGoogle Scholar
- Firbank SJ, Wardle J, Heslop P, Lewis RJ, Connolly BA: Uracil recognition in archaeal DNA polymerases captured by X-ray crystallography. J Mol Biol. 2008, 381: 529-539.PubMedView ArticleGoogle Scholar
- Masumoto H, Sugino A, Araki H: Dpb11 controls the association between DNA polymerases alpha and epsilon and the autonomously replicating sequence region of budding yeast. Mol Cell Biol. 2000, 20: 2809-2817.PubMedPubMed CentralView ArticleGoogle Scholar
- Baranovskiy AG, Babayeva ND, Liston VG, Rogozin IB, Koonin EV, Pavlov YI, Vassylyev DG, Tahirov TH: X-ray structure of the complex of regulatory subunits of human DNA polymerase delta. Cell Cycle. 2008, 7: 3026-3036.PubMedPubMed CentralView ArticleGoogle Scholar
- Wardle J, Burgers PM, Cann IK, Darley K, Heslop P, Johansson E, Lin LJ, McGlynn P, Sanvoisin J, Stith CM, Connolly BA: Uracil recognition by replicative DNA polymerases is limited to the archaea, not occurring with bacteria and eukarya. Nucleic Acids Res. 2008, 36: 705-711.PubMedPubMed CentralView ArticleGoogle Scholar
- Pruitt KD, Tatusova T, Maglott DR: NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 2007, 35: D61-65.PubMedPubMed CentralView ArticleGoogle Scholar
- Pei J, Kim BH, Tang M, Grishin NV: PROMALS web server for accurate multiple protein sequence alignments. Nucleic Acids Res. 2007, 35: W649-652.PubMedPubMed CentralView ArticleGoogle Scholar
- Edgar RC: MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004, 32: 1792-1797.PubMedPubMed CentralView ArticleGoogle Scholar
- Schneider TD, Stormo GD, Gold L, Ehrenfeucht A: Information content of binding sites on nucleotide sequences. J Mol Biol. 1986, 188: 415-431.PubMedView ArticleGoogle Scholar
- Crooks GE, Hon G, Chandonia JM, Brenner SE: WebLogo: a sequence logo generator. Genome Res. 2004, 14: 1188-1190.PubMedPubMed CentralView ArticleGoogle Scholar
- McGuffin LJ, Bryson K, Jones DT: The PSIPRED protein structure prediction server. Bioinformatics. 2000, 16: 404-405.PubMedView ArticleGoogle Scholar
- Adachi J, Hasegawa M: MOLPHY: Programs for Molecular Phylogenetics. 1992, Tokyo: Institute of Statistical MathematicsGoogle Scholar
- Adachi J, Waddell PJ, Martin W, Hasegawa M: Plastid genome phylogeny and a model of amino acid substitution for proteins encoded by chloroplast DNA. J Mol Evol. 2000, 50: 348-358.PubMedGoogle Scholar
- Felsenstein J: Inferring phylogenies from protein sequences by parsimony, distance, and likelihood methods. Methods Enzymol. 1996, 266: 418-427.PubMedView ArticleGoogle Scholar
- Jobb G, von Haeseler A, Strimmer K: TREEFINDER: a powerful graphical analysis environment for molecular phylogenetics. BMC Evol Biol. 2004, 4: 18-PubMedPubMed CentralView ArticleGoogle Scholar
- Stamatakis A: RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Bioinformatics. 2006, 22: 2688-2690.PubMedView ArticleGoogle Scholar
- Forterre P: Three RNA cells for ribosomal lineages and three DNA viruses to replicate their genomes: a hypothesis for the origin of cellular domain. Proc Natl Acad Sci USA. 2006, 103: 3669-3674.PubMedPubMed CentralView ArticleGoogle Scholar
- Villarreal LP, DeFilippis VR: A hypothesis for DNA viruses as the origin of eukaryotic replication proteins. J Virol. 2000, 74: 7079-7084.PubMedPubMed CentralView ArticleGoogle Scholar
- Filee J, Forterre P, Laurent J: The role played by viruses in the evolution of their hosts: a view based on informational protein phylogenies. Res Microbiol. 2003, 154: 237-243.PubMedView ArticleGoogle Scholar
- Maki S, Hashimoto K, Ohara T, Sugino A: DNA polymerase II (epsilon) of Saccharomyces cerevisiae dissociates from the DNA template by sensing single-stranded DNA. J Biol Chem. 1998, 273: 21332-21341.PubMedView ArticleGoogle Scholar
- Tsubota T, Maki S, Kubota H, Sugino A, Maki H: Double-stranded DNA binding properties of Saccharomyces cerevisiae DNA polymerase epsilon and of the Dpb3p-Dpb4p subassembly. Genes Cells. 2003, 8: 873-888.PubMedView ArticleGoogle Scholar
- Evanics F, Maurmann L, Yang WW, Bose RN: Nuclear magnetic resonance structures of the zinc finger domain of human DNA polymerase-alpha. Biochim Biophys Acta. 2003, 1651: 163-171.PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.