Human DNA polymerase kappa synthesizes DNA with extraordinarily low fidelity

Zhang, Y.

doi:10.1093/nar/28.21.4147

Cited by 108 publications

(102 citation statements)

References 39 publications

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“…When nucleotides containing dG-N 2 -BPDE, the most potent carcinogenic compound produced by industrial and cigarette smoke, are used as template, Polκ can bypass the adduct with much higher efficiency than Polη or Polι by correctly inserting C opposite the bulky lesion [114]. However, when undamaged DNA or DNA containing some common lesions is used as template, Polκ exhibits extraordinarily low fidelity [115][116][117].…”

Section: Y Family Dna Polymerasesmentioning

confidence: 99%

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Andersen¹,

Xiao³

2007

Cell Res

185

187

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npg In addition to well-defined DNA repair pathways, all living organisms have evolved mechanisms to avoid cell death caused by replication fork collapse at a site where replication is blocked due to disruptive covalent modifications of DNA. The term DNA damage tolerance (DDT) has been employed loosely to include a collection of mechanisms by which cells survive replication-blocking lesions with or without associated genomic instability. Recent genetic analyses indicate that DDT in eukaryotes, from yeast to human, consists of two parallel pathways with one being error-free and another highly mutagenic. Interestingly, in budding yeast, these two pathways are mediated by sequential modifications of the proliferating cell nuclear antigen (PCNA) by two ubiquitination complexes Rad6-Rad18 and Mms2-Ubc13-Rad5. Damage-induced monoubiquitination of PCNA by Rad6-Rad18 promotes translesion synthesis (TLS) with increased mutagenesis, while subsequent polyubiquitination of PCNA at the same K164 residue by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Data obtained from recent studies suggest that the above mechanisms are conserved in higher eukaryotes. In particular, mammals contain multiple specialized TLS polymerases. Defects in one of the TLS polymerases have been linked to genomic instability and cancer. DNA damage toleranceIn the presence of spontaneous or carcinogen-induced DNA damage, living cells have to maintain and complete DNA synthesis or risk replication fork collapse. Since the process of DNA licensing is to ensure the genome is duplicated once and only once during each cell cycle, stalled or collapsed replication forks may not be able to restart, which often results in double-strand breaks (DSBs) and causes compromised genome integrity or cell death. In addition to highly conserved DNA repair pathways, all living organisms have evolved schemes to ensure continuation of DNA synthesis in the presence of damage. These schemes were originally termed DNA postreplication repair (PRR) due to observations of transient shortened nascent DNA structures following S phase in response to DNA damage. In bacteria and unicellular yeast, these shortened DNA segments can be measured by an alkaline sedimentation assay [1] or directly observed in electron micrographs [2]. In wild-type cells, these truncated DNA segments were restored to full length following a short recovery time. One typical experiment [1] involved the restoration of the nascent strand following UV exposure in nucleotide excision repair (NER)-deficient cells and was originally assumed to represent a mechanism of DNA repair. However, further investigation revealed that, although the nascent fragments were re-annealed, the original UV-induced pyrimidine dimers, which were responsible for the generation of single-strand gaps, often persisted in the genome [3,4]. It was argued that the replication-blocking lesion was not necessarily corrected, but rather transiently bypassed and carried over to the next generation. Perhaps it is more beneficial for the organi...

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Section: Y Family Dna Polymerasesmentioning

confidence: 99%

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Andersen¹,

Xiao³

2007

Cell Res

185

187

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“…Preparation of DNA primer-template: The 15-mer primer was 5' end-labeled with [γ- 32 100 µg BSA/mL, and 10% glycerol. Replication reactions with pol α were incubated at 30°C, and those with pols β, η, and κ were incubated at 37°C.…”

Section: Primer Extension Assaysmentioning

confidence: 99%

8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

Medina

Zhang

et al. 2002

Biochemistry

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“…in a T:G mismatch, where the thymine residue was formed by deamination of 5-methylcytosine (53). pol has the ability to bypass some lesions in vitro (47,48), and like the other DNA polymerases of its family, it is highly mutagenic on undamaged DNA (46,52,54). However, its biological function is still unknown.…”

Section: An Overview Of Translesion Replication Systemsmentioning

confidence: 99%

DNA Damage Control by Novel DNA Polymerases: Translesion Replication and Mutagenesis

Livneh¹

2001

Journal of Biological Chemistry

117

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DNA is constantly subjected to injuries inflicted by external agents such as UV light or cigarette smoke, by intracellular byproducts of metabolism such as reactive oxygen species, or by spontaneous decay. DNA lesions interfere with replication and with transcription and if left in DNA can cause mutation, malfunction, and cell death. These deleterious effects are usually prevented by DNA repair mechanisms, which remove the damaged nucleotide and restore the original DNA sequence (for review, see Ref. 1). However, the repair mechanisms are not fully efficient, and some lesions persist in the DNA. The attempt to replicate such unrepaired lesions usually leads to an interruption of replication and to the formation of a ssDNA 1 region carrying the damaged nucleotide, a gap-lesion structure.Filling in of gap-lesion structures can be done by one of two known mechanisms: recombinational repair and translesion replication. Recombinational repair consists of patching the gap with a DNA segment that was cut out from the undamaged strand in the fully replicated sister chromatid (2, 3). This converts the damaged region into the dsDNA form, enabling a second attempt of errorfree repair. Alternatively, the gap may be filled in by DNA synthesis, a process that is inherently mutagenic because of the miscoding nature of most damaged nucleotides. This pathway was, therefore, termed translesion replication (TLR 2 ), translesion synthesis, errorprone repair, mutagenic repair, bypass synthesis, or lesion bypass (4 -6). A third mechanism that may exist was termed copy choice replication, but only little is known about it (7-9). In the last 2 years a major breakthrough has occurred with the discovery that TLR is carried out by specialized DNA polymerases that belong to a novel superfamily. These DNA polymerases, which were found in a number of organisms ranging from Escherichia coli to humans, exhibit a high frequency of errors during in vitro DNA synthesis. Some of them clearly function in TLR, whereas the functions of others are unknown yet (for recent reviews, see . This review will present an overview of the new DNA polymerases, focus on E. coli DNA polymerase V and human DNA polymerase , and conclude with a discussion of some general issues in TLR. An Overview of Translesion Replication SystemsIn E. coli TLR is regulated by the SOS response. The main component of this reaction is one of the novel DNA polymerases, a product of the umuC gene termed pol V (15, 16). 3 The umuC gene is a typical SOS gene, which is repressed by LexA and induced by RecA (for a review on the SOS system see Ref. 1). The lesion bypass activity of pol V requires three additional proteins: UmuDЈ, a shorter form of UmuD formed by RecA-mediated proteolysis (17), RecA, and SSB (15,16). In addition, it is stimulated by the processivity subunits of pol III, namely the ␤ subunit sliding clamp and the ␥ complex clamp loader (15). Based on genetic evidence pol V is the main lesion bypass polymerase in E. coli. Inactivating TLR by a umuC mutation leads to a modest re...

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Human DNA polymerase kappa synthesizes DNA with extraordinarily low fidelity

Cited by 108 publications

References 39 publications

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

DNA Damage Control by Novel DNA Polymerases: Translesion Replication and Mutagenesis

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Human DNA polymerase kappa synthesizes DNA with extraordinarily low fidelity

Cited by 108 publications

References 39 publications

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

8-(Hydroxymethyl)-3,N4-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

DNA Damage Control by Novel DNA Polymerases: Translesion Replication and Mutagenesis

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8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases