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Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A DNA polymerase with a 3'-to 5'-exonuclease that copurified with polymerase-primase from calf thymus was purified and extensively characterized. Its exonuclease degraded single-stranded DNA from 3' to 5' in a strictly distributive manner. On synthetic template-primer junctions, 3'-terminal mispairs were excised with a 10- to 20-fold preference over correctly paired nucleotides. In comparison to the 3'- to 5'-exonuclease the DNA polymerase activity was rather low. The ratio of nucleotides incorporated to nucleotides excised was in the order of 1 to 3 nucleotide insertions per excision, suggesting that net forward DNA synthesis is not the primary role of this DNA polymerase. DNA synthesis was performed with a low processivity in the presence and absence of PCNA. Both the polymerase and exonuclease activities were inhibited to a comparable extent by AMP. Thus, the exonuclease-polymerase might represent a novel DNA polymerase that we tentatively designate as DNA polymerase zeta. Possible benefits of DNA polymerase zeta in the process of error correction and the apparent dichotomy of an built-in proofreading activity for the processive DNA polymerases gamma, delta, and epsilon and an obviously external proofreading function for the less processive animal cell DNA polymerases alpha and beta are discussed.
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PMID:An error-correcting proofreading exonuclease-polymerase that copurifies with DNA-polymerase-alpha-primase. 838 85

The REV3 and REV7 genes of the yeast Saccharomyces cerevisiae are required for DNA damage-induced mutagenesis. The Rev3 and Rev7 proteins were shown to form a complex with DNA polymerase activity. This polymerase replicated past a thymine-thymine cis-syn cyclobutane dimer, a lesion that normally severely inhibits replication, with an efficiency of approximately 10 percent. In contrast, bypass replication efficiency with yeast DNA polymerase alpha was no more than 1 percent. The Rev3-Rev7 complex is the sixth eukaryotic DNA polymerase to be described, and is therefore called DNA polymerase zeta.
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PMID:Thymine-thymine dimer bypass by yeast DNA polymerase zeta. 865 38

DNA damage induced mutations arising during the course of translesion replication are likely to be an important contributory cause in the development of many cancers. In budding yeast, Saccharomyces cerevisiae, a good model system with which to investigate this process, mutagenesis is associated with the RAD6 repair pathway and depends on the functions of the REV1, REV3 and REV7 genes. The Rev3 and Rev7 proteins are subunits of a new type of DNA polymerase, called DNA polymerase zeta, that appears to carry out translesion replication, but no other repair, recombination or replication function. Pol zeta replicates past a T-T cyclobutane dimer with a higher efficiency than yeast pol alpha, is less prone than this enzyme to insert an incorrect nucleotide and is more efficient at elongating from a mismatched terminus. Rev1 protein is a terminal nucleotidyl transferase that inserts dCMP opposite template G, A and abasic sites. Types of mutations induced during translesion replication appear to depend largely on lesion structure, but the frequency and accuracy of bypass also depend on replication conditions. Inhibition of the activity or expression of pol zeta may be clinically useful for patients undergoing cancer therapy or for those with a familial predisposition to cancer.
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PMID:DNA polymerase zeta and the control of DNA damage induced mutagenesis in eukaryotes. 897 26

There are five well-characterized nuclear DNA polymerases in eukaryotes (DNA polymerases alpha, beta, delta, epsilon and zeta) and this short review summarizes our current knowledge concerning the participation of each in DNA-repair. The three major DNA excision-repair pathways involve a DNA synthesis step that replaces altered bases or nucleotides removed during repair. Base excision-repair removes many modified bases and abasic sites, and in mammalian cells this mainly involves DNA polymerase beta. An alternative means for completion of base excision-repair, involving DNA polymerases delta or epsilon, may also operate and be even more important in yeast. Nucleotide excision-repair uses DNA polymerases delta or epsilon to resynthesize the bases removed during repair of pyrimidine dimers and other bulky adducts in DNA. Similarly, mismatch-repair of replication errors appears to involve DNA polymerases delta or epsilon. DNA polymerase alpha is required for semi-conservative replication of DNA but not for repair of DNA. A more recently discovered enzyme, DNA polymerase zeta, appears to be involved in the bypass of damage, without excision, and occurs during DNA replication of a damaged template.
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PMID:Which DNA polymerases are used for DNA-repair in eukaryotes? 911 Nov 89

Recombinational repair of double-strand breaks (DSBs), traditionally believed to be an error-free DNA repair pathway, was recently shown to increase the frequency of mutations in a nearby interval. The reversion rate of trp1 alleles (either nonsense or frameshift mutations) near an HO-endonuclease cleavage site is increased at least 100-fold among cells that have experienced an HO-mediated DSB. We report here that in strains deleted for rev3 this DSB-associated reversion of a nonsense mutation was greatly decreased. Thus REV3, which encodes a subunit of the translesion DNA polymerase zeta, was responsible for the majority of these base substitution errors near a DSB. However, rev3 strains showed no decrease in HO-stimulated recombination, implying that another DNA polymerase also functioned in recombinational repair of a DSB. Reversion of trp1 frameshift alleles near a DSB was not reduced in rev3 strains, indicating that another polymerase could act during DSB repair to make these frameshift errors. Analysis of spontaneous reversion in haploid strains suggested that Rev3p had a greater role in making point mutations than in frameshift mutations.
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PMID:A role for REV3 in mutagenesis during double-strand break repair in Saccharomyces cerevisiae. 938 49

To get a better understanding of mutagenic mechanisms in humans, we have cloned and sequenced the human homolog of the Saccharomyces cerevisiae REV3 gene. The yeast gene encodes the catalytic subunit of DNA polymerase zeta, a nonessential enzyme that is thought to carry out translesion replication and is responsible for virtually all DNA damage-induced mutagenesis and the majority of spontaneous mutagenesis. The human gene encodes an expected protein of 3,130 residues, about twice the size of the yeast protein (1,504 aa). The two proteins are 29% identical in an amino-terminal region of approximately 340 residues, 39% identical in a carboxyl-terminal region of approximately 850 residues, and 29% identical in a 55-residue region in the middle of the two genes. The sequence of the expected protein strongly predicts that it is the catalytic subunit of a DNA polymerase of the pol zeta type; the carboxyl-terminal domain possesses, in the right order, the six motifs characteristic of eukaryotic DNA polymerases, most closely resembles yeast pol zeta among all polymerases in the GenBank database, and is different from the human alpha, delta, and epsilon enzymes. Human cells expressing high levels of an hsREV3 antisense RNA fragment grow normally, but show little or no UV-induced mutagenesis and are slightly more sensitive to killing by UV. The human gene therefore appears to carry out a function similar to that of its yeast counterpart.
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PMID:A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta. 961 6

DNA polymerases carry out a large variety of synthetic transactions during DNA replication, DNA recombination and DNA repair. Substrates for DNA polymerases vary from single nucleotide gaps to kilobase size gaps and from relatively simple gapped structures to complex replication forks in which two strands need to be replicated simultaneously. Consequently, one would expect the cell to have developed a well-defined set of DNA polymerases with each one uniquely adapted for a specific pathway. And to some degree this turns out to be the case. However, in addition we seem to find a large degree of cross-functionality of DNA polymerases in these different pathways. DNA polymerase alpha is almost exclusively required for the initiation of DNA replication and the priming of Okazaki fragments during elongation. In most organisms no specific repair role beyond that of checkpoint control has been assigned to this enzyme. DNA polymerase delta functions as a dimer and, therefore, may be responsible for both leading and lagging strand DNA replication. In addition, this enzyme is required for mismatch repair and, together with DNA polymerase zeta, for mutagenesis. The function of DNA polymerase epsilon in DNA replication may be restricted to that of Okazaki fragment maturation. In contrast, either polymerase delta or epsilon suffices for the repair of UV-induced damage. The role of DNA polymerase beta in base-excision repair is well established for mammalian systems, but in yeast, DNA polymerase delta appears to fulfill that function.
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PMID:Eukaryotic DNA polymerases in DNA replication and DNA repair. 974 46

DNA damage can cause mutations which in turn may lead to carcinogenesis. In the yeast Saccharomyces cerevisiae, DNA damage-induced mutagenesis pathway requires the REV3 gene. It encodes the catalytic subunit of DNA polymerase zeta that specifically functions in translesion DNA synthesis. We have cloned a cDNA of the human homologue of REV3 (hREV3), which consists of 10,716 bp and codes for a protein of 3130 amino acid residues (352,737 Da). Its C-terminal 755 amino acids show extensive homology with the yeast protein at the C-terminus: 43% identity and 74% similarity. This region contains the six highly conserved DNA polymerase motifs. Furthermore, we have identified four sequence motifs in the N-terminal region outside the polymerase domain that are conserved in DNA polymerase delta from various sources. Three of which are present in DNA polymerase zeta encoded by human, yeast, and plant REV3 genes, indicating that this protein is a member of the DNA polymerase delta family. DNA polymerases delta and zeta are structurally distinguished by the presence of a specific delta IV motif in the former and motifs zeta I and zeta II in the latter, respectively. Human DNA polymerase zeta is ubiquitously expressed in various tissues, consistent with the notion that the hREV3 pathway may be a fundamental mechanism of damage-induced mutagenesis in humans.
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PMID:A full-length cDNA of hREV3 is predicted to encode DNA polymerase zeta for damage-induced mutagenesis in humans. 1010 35

Cells that have been irradiated with ultraviolet light (UV) suffer damage to their DNA, primarily in the form of covalent linkage between adjacent pyrimidines. Such photoproducts represent blocks to RNA and DNA polymerases and are potentially mutagenic. Blockage of RNA polymerase II by a photoproduct in the transcribed strand of an active gene leads to induction of the p53 protein, which induces pleiotropic responses that may include apoptotic cell death. If a cell survives, the blocked polymerase targets the nucleotide excision repair machinery to the site of the lesion, which is repaired in an error-free manner. Repair coupled to transcription in this manner strongly influences the mutation spectrum induced by UV, reducing the proportion of base substitutions that arise from photoproducts on the transcribed strand. If the damage persists when the DNA is replicated in S-phase, either because the cell is unable to repair the damage or because there is insufficient time between the induction of damage and the onset of S-phase. To do so, the replicative DNA polymerase complex may be blocked. In this situation, lesion bypass can be accomplished using an error-free mechanism, or using an error-prone mechanism that involves the newly described, non-processive DNA polymerase zeta encoded by the human homolog of the yeast REV3 gene.
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PMID:DNA repair, DNA replication, and UV mutagenesis. 1053 99

DNA polymerase zeta (Pol zeta) and Rev1p carry out translesion replication in budding yeast, Saccharomyces cerevisiae, and are jointly responsible for almost all base pair substitution and frameshift mutations induced by DNA damage in this organism. In addition, Pol zeta is responsible for the majority of spontaneous mutations in yeast and has been proposed as the enzyme responsible for somatic hypermutability. Pol zeta, a non-processive enzyme that lacks a 3' to 5' exonuclease proofreading activity, is composed of Rev3p, the catalytic subunit, and a second subunit encoded by REV7. In keeping with its role, extension by Pol zeta is relatively tolerant of abnormal DNA structure at the primer terminus and is much more capable of extension from terminal mismatches than yeast DNA polymerase alpha (Pol alpha). Rev1p is a bifunctional enzyme that possesses a deoxycytidyl transferase activity that incorporates deoxycytidyl opposite abasic sites in the template and a second, at present poorly defined, activity that is required for the bypass of a variety of lesions as well as abasic sites. Human homologues of the yeast REV1 and REV3 have been identified and, based on the phenotype of cells producing antisense RNA to one or other of these genes, their products appear also to be employed in translation replication and spontaneous mutagenesis. We suggest that Pol zeta is best regarded as a replication enzyme, albeit one that is used only intermittently, that promotes extension at forks the progress of which is blocked for any reason, whether the presence of an unedited terminal mismatch or unrepaired DNA lesion.
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PMID:Mutagenesis in eukaryotes dependent on DNA polymerase zeta and Rev1p. 1120 28


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