The mutagenic potential of non-homologous end joining in the absence of the NHEJ core factors Ku70/80, DNA-PKcs and XRCC4-LigIV.

Abstract:

:Non-homologous end joining (NHEJ), the major pathway of double-strand break (DSB) repair in mammalian cells, comprises two subpathways: one that requires the three core factors Ku70/80, DNA-PKcs and XRCC4/LigIV (DNA-PK-dependent NHEJ) and the other that is independent of these factors. Using a cell-free NHEJ assay, we have investigated the ability of three Chinese hamster ovary (CHO) mutants deficient in Ku80 (xrs6), DNA-PKcs (XR-C1) and XRCC4 (XR-1) in comparison with CHO-K1 wild-type cells to rejoin non-compatible DSB ends. Both NHEJ efficiency and fidelity are strongly reduced in the mutants with xrs6 and XR-1 exhibiting the strongest reduction and XR-C1 displaying a phenotype intermediate between the wild-type and the other two mutants indicating a non-essential but facilitating role of DNA-PKcs in NHEJ. The decrease in fidelity in the mutants is expressed by an increase of deletion junctions formed at microhomologies (microhom) near the DSB (microhomology-mediated non-homologous end joining: microhomNHEJ). Using a novel microhomNHEJ assay, we show that microhom regions of 6-10 bp that are located directly at the DSB termini strongly enhance the mutagenic microhomNHEJ reaction even in the wild type. Due to its error proneness, DNA-PK-independent microhomNHEJ may actively promote genome instability. It will, therefore, be of increasing importance to examine NHEJ fidelity in the context with tumorigenesis and cellular senescence for which we here provide two efficient and reliable tools.

journal_name

Mutagenesis

journal_title

Mutagenesis

authors

Kuhfittig-Kulle S,Feldmann E,Odersky A,Kuliczkowska A,Goedecke W,Eggert A,Pfeiffer P

doi

10.1093/mutage/gem007

subject

Has Abstract

pub_date

2007-05-01 00:00:00

pages

217-33

issue

3

eissn

0267-8357

issn

1464-3804

pii

gem007

journal_volume

22

pub_type

杂志文章
  • A modified protocol for the cytochalasin B in vitro micronucleus assay using whole human blood or separated lymphocyte cultures.

    abstract::A modified protocol is described for the in vitro analysis of micronuclei in whole blood or separated lymphocyte cultures. The induction of binucleate cells by various concentrations of cytochalasin B (3, 4.5 or 6 micrograms/ml) was examined at two harvest times (68 or 72 h). An optimal yield was obtained by adding cy...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/8.4.317

    authors: Ellard S,Parry EM

    更新日期:1993-07-01 00:00:00

  • Metabolic formation, synthesis and genotoxicity of the N-hydroxy derivative of the food mutagen 2-amino-1-methyl-6-phenylimidazo (4,5-b) pyridine (PhIP).

    abstract::Hepatic microsomes from rats pretreated with PCB were found to metabolize the food mutagen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) to two major metabolites, one of which was identified as the N-hydroxy derivative, 2-hydroxy-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (N-OH-PhIP). This identification w...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/6.1.93

    authors: Frandsen H,Rasmussen ES,Nielsen PA,Farmer P,Dragsted L,Larsen JC

    更新日期:1991-01-01 00:00:00

  • Induction of sister chromatid exchanges and cell division delays in human lymphocytes by the anti-tumour agent homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenoxy acetic acid.

    abstract::3 beta-Hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl) aminophenoxyacetate (NSC 294859) is a new modified steroidal alkylating agent. This compound was given by i.p. administration to mice bearing different types of tumour. It was found to exhibit good activity in L1210 and...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/4.5.361

    authors: Tselepi MR,Demopoulos NA,Catsoulacos P

    更新日期:1989-09-01 00:00:00

  • Randomized controlled trial: effects of diet on DNA damage in heavy smokers.

    abstract::We have conducted a randomized trial which investigated the ability of dietary changes (in particular diets rich in cruciferous vegetables and flavonoids), to increase urinary antimutagenicity and inhibit DNA damage in smokers. Ninety heavy smokers were recruited and randomly assigned to three groups, and were given t...

    journal_title:Mutagenesis

    pub_type: 杂志文章,随机对照试验

    doi:10.1093/mutage/gel021

    authors: Talaska G,Al-Zoughool M,Malaveille C,Fiorini L,Schumann B,Vietas J,Peluso M,Munnia A,Bianchini M,Allegro G,Matullo G,Sacerdote C,Vineis P

    更新日期:2006-05-01 00:00:00

  • Meta-analysis of the effect of HHEX gene polymorphism on the risk of type 2 diabetes.

    abstract::In the past decade, a number of case-control studies have been carried out to investigate the relationship between the HHEX polymorphism and type 2 diabetes (T2D). However, the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the rela...

    journal_title:Mutagenesis

    pub_type: 杂志文章,meta分析

    doi:10.1093/mutage/geq095

    authors: Cai Y,Yi J,Ma Y,Fu D

    更新日期:2011-03-01 00:00:00

  • Possible methodologies for the detection and study of DNA sequence changes following mutagen exposure: magnetic enrichment in mutant DNA.

    abstract::The restriction site mutation method described by Parry et al. (1990) for isolating mutant sequences directly from DNA is discussed and an additional enrichment step proposed using magnetic beads. ...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/5.6.523

    authors: Bridges BA,Carr AM,Lehmann AR

    更新日期:1990-11-01 00:00:00

  • A test of the mutagenicity of cooked meats in vivo.

    abstract::There is a correlation between intestinal cancer and diets high in meat, so fried beef, chicken, lamb, pork and fish were tested for their ability to induce mutations in the small intestine of mice. The mice were bred to be heterozygous at the Dlb-1 locus so that loss of the dominant Dlb-1 b allele by mutation could b...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/16.2.103

    authors: Heddle JA,Knize MG,Dawod D,Zhang XB

    更新日期:2001-03-01 00:00:00

  • Butylated hydroxytoluene does not protect Chinese hamster ovary cells from chromosomal damage induced by high-dose rate 192Ir irradiation.

    abstract::Previous reports showed the protective effect of the synthetic antioxidant butylated hydroxytoluene (BHT) against the chromosomal damage induced by bleomycin (BLM), cadmium chloride and potassium dichromate. To test the hypothesis that this effect was exerted by inhibition and/or scavenging of reactive oxygen species ...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/gel046

    authors: Grillo CA,Dulout FN

    更新日期:2006-11-01 00:00:00

  • Baseline levels of chromosome instability in the human lymphoblastoid cell TK6.

    abstract::Induced genomic instability in the human B lymphoblastoid cell line TK6 manifests itself as increases in end-to-end chromosome fusions and non-reciprocal chromosome translocations. It is not associated with elevated frequencies of specific locus mutations or other cytogenetic alterations. Previous studies on a limited...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/geh060

    authors: Schwartz JL,Jordan R,Evans HH,Lenarczyk M,Liber HL

    更新日期:2004-11-01 00:00:00

  • A proposal for a two-dose/single-sample in vivo/in vitro rat hepatocyte unscheduled DNA synthesis assay.

    abstract::We have developed a two dose/single-sample protocol for the in vivo/in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay. In order to enhance the effectiveness of grain detection by image analysis we found minor technical modifications to be beneficial. These included the use of 3% acetic acid in ethanol (or ...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/11.1.19

    authors: Amphlett NW,Mitchell ID,Rees RW,Haynes GA

    更新日期:1996-01-01 00:00:00

  • Numerical and structural chromosome aberrations induced by etoposide (VP16) during oocyte maturation of mice: transmission to one-cell zygotes and damage to dictyate oocytes.

    abstract::The antineoplastic drug etoposide (ET) inhibits topoisomerase II (topo II) activity by forming a ternary complex (DNA-ET-topo II). This complex prevents the DNA-strand-rejoining activity of topo II and may result in structural chromosome aberrations. Inhibition of topo II activity may also predispose cells to aneuploi...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/11.4.357

    authors: Mailhes JB,Marchetti F,Young D,London SN

    更新日期:1996-07-01 00:00:00

  • O6-methylguanine-DNA methyltransferase activities from exponentially growing human T lymphocytes: similar activities in controls and Alzheimer's disease patients.

    abstract::O6-Methylguanine-DNA methyltransferase (MT) specific activity (fmol/mg protein) was measured in human T lymphocytes which were maintained as exponentially growing cultures from 6 to 17 days. The T lymphocytes were not transformed and were grown under the same conditions used previously for determination of spontaneous...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/5.2.169

    authors: Bartlett JD,Robison SH

    更新日期:1990-03-01 00:00:00

  • Alternatives to Aroclor 1254-induced S9 in in vitro genotoxicity assays.

    abstract::A working party was set up by the UK Environmental Mutagen Society to consider alternatives to Aroclor 1254 (Aroclor)-induced S9 in in vitro genotoxicity assays, with the aims of considering whether a replacement for Aroclor in its role in general screening assays could be readily identified. The working party conclud...

    journal_title:Mutagenesis

    pub_type:

    doi:10.1093/mutage/7.3.175

    authors: Elliott BM,Combes RD,Elcombe CR,Gatehouse DG,Gibson GG,Mackay JM,Wolf RC

    更新日期:1992-05-01 00:00:00

  • Partial pronase digestion of rat gastric mucosa isolates cells undergoing replicative DNA synthesis.

    abstract::A pronase digestion procedure for the isolation of gastric mucosal cells was evaluated for its usefulness in measuring unscheduled DNA synthesis (UDS). The method has been claimed to be suited for assessing the genotoxicity potential of compounds. Compounds were given orally to rats. After 13 h [3H]thymidine was injec...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/6.1.3

    authors: Larsson H,Fryklund J,Helander HF,Wallmark B

    更新日期:1991-01-01 00:00:00

  • In vitro and in vivo evaluation of the antihypertensive drug atenolol in cultured human lymphocytes: effects of long-term therapy.

    abstract::The genotoxicity of atenolol, a beta-blocker antihypertensive drug, both in vitro and in vivo, was cytogenetically tested for its ability to induce sister chromatid exchange (SCE) and micronuclei (MN) in cultured peripheral lymphocytes. Also, fluorescence in situ hybridization (FISH) with a centromeric probe was perfo...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/15.3.195

    authors: Télez M,Martínez B,Criado B,Lostao CM,Penagarikano O,Ortega B,Flores P,Ortiz-Lastra E,Alonso RM,Jiménez RM,Arrieta I

    更新日期:2000-05-01 00:00:00

  • Combined treatment with 4-(N-methyl-N-nitrosamino)-1- (3-pyridyl)-1-butanone and dibutyl phthalate enhances ozone-induced genotoxicity in B6C3F1 mice.

    abstract::Potential toxicological interactions of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and/or dibutyl phthalate (DBP) with ozone were investigated. Male and female B6C3F1 mice were exposed to ozone (0.5 p.p.m.), NNK (1.0 mg/kg), DBP (5000 p.p.m.) and different combinations of these toxicants 6 h/day for 16,...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/17.4.331

    authors: Kim MY,Kim YC,Cho MH

    更新日期:2002-07-01 00:00:00

  • Is habitual alcohol drinking associated with reduced electrophoretic DNA migration in peripheral blood leukocytes from ALDH2-deficient male Japanese?

    abstract::Alcohol drinking-derived acetaldehyde is believed to cross-link DNA and induce sister chromatid exchanges in peripheral blood lymphocytes. However, little population data are available to illustrate effects of alcohol-derived acetaldehyde on DNA migration as assayed by the comet assay in peripheral lymphocytes. In the...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/gep008

    authors: Lu Y,Morimoto K

    更新日期:2009-07-01 00:00:00

  • Vitamin D3 as adjuvant in the treatment of type 2 diabetes mellitus: modulation of genomic and biochemical instability.

    abstract::Type 2 diabetes mellitus has undergone a worldwide growth in incidence in the world and has now acquired epidemic status. There is a strong link between type 2 diabetes and vitamin D deficiency. Because vitamin D has beneficial effects on glucose homeostasis, the aim of this study was to evaluate the influence of vita...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/gez001

    authors: Fagundes GE,Macan TP,Rohr P,Damiani AP,Da Rocha FR,Pereira M,Longaretti LM,Vilela TC,Ceretta LB,Mendes C,Silveira PCL,Teixeira JPF,de Andrade VM

    更新日期:2019-05-29 00:00:00

  • Tripterygium hypoglaucum (level) Hutch induces aneuploidy of chromosome 8 in mouse bone marrow cells and sperm.

    abstract::Aneuploidy of mouse chromosome 8 induced by a Chinese medicinal herb, Tripterygium hypoglaucum (level) Hutch (THH) was investigated by fluorescence in situ hybridization (FISH) in vivo. Male mice were treated with THH (single i.p. injection) at doses of 120, 240 and 480 mg/kg. Colchicine (COL, 1.5 mg/kg i.p.) was used...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/geh044

    authors: Xu W,Ziqing L,Yinrun D,Xiaoyan W,Jinglun X

    更新日期:2004-09-01 00:00:00

  • Photomutagenicity assays in bacteria: factors affecting assay design and assessment of photomutagenic potential of para-aminobenzoic acid.

    abstract::Photomutagenicity assays are required for regulatory submissions of some chemicals. As yet there are no well-validated protocols available for these assays. Critical factors which may contribute to the ability of a bacterial assay to detect photomutagens (e.g. dose of UV and test chemical, exposure conditions, light s...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/9.5.459

    authors: Henderson L,Fedyk J,Bourner C,Windebank S,Fletcher S,Lovell W

    更新日期:1994-09-01 00:00:00

  • Biological significance of DNA damage induced by hyperbaric oxygen.

    abstract::Hyperbaric oxygen (HBO) treatment as used therapeutically has been shown to induce DNA damage in the alkaline comet assay with leukocytes from test subjects. Using formamidopyrimidine-DNA glycosylase, a DNA repair enzyme which specifically nicks DNA at sites of 8-oxoguanines and formamidopyrimidines, we have detected ...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/13.1.85

    authors: Speit G,Dennog C,Lampl L

    更新日期:1998-01-01 00:00:00

  • A comparison of folic acid and 5-methyltetrahydrofolate for prevention of DNA damage and cell death in human lymphocytes in vitro.

    abstract::Folic acid (FA), the most oxidized and stable form of folate, is commonly used as a dietary supplement and in culture media. FA must be reduced and methylated to become the metabolically active form found in blood and utilized by tissues, i.e. 5-methyltetrahydrofolate (5-MeTHF). 5-MeTHF is the methyl group donor requi...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/18.1.81

    authors: Wang X,Fenech M

    更新日期:2003-01-01 00:00:00

  • On the mechanism of mitotic segregation induction in Aspergillus nidulans by benzene hydroxy metabolites.

    abstract::The principal hydroxy-metabolites of benzene--hydroquinone, catechol and phenol--were assayed in tests for mitotic segregation induction in Aspergillus nidulans diploid strain 19. Hydroquinone was the most effective chemical, increasing the frequency of mitotic segregants up to 10-fold at 1-3 mM. Catechol was similarl...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/2.3.235

    authors: Crebelli R,Conti G,Carere A

    更新日期:1987-05-01 00:00:00

  • Sodium arsenite-induced chromosomal aberrations in the Xq arm of Chinese hamster cell lines.

    abstract::Non-cytotoxic concentrations (1.5, 3 and 6 microM) of sodium arsenite (SA) were used to study its cytogenetic effects with special reference to the frequency and nature of chromosomal aberrations on the X chromosome at Xq21 and at centromeric regions in CHO9, EM-C11, V79, V-H4 and CHE cell lines using Giemsa and FISH ...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/13.3.229

    authors: Radha S,Natarajan AT

    更新日期:1998-05-01 00:00:00

  • The 3D reconstructed skin micronucleus assay: considerations for optimal protocol design.

    abstract::Implementation of the seventh amendment to the EU Cosmetics Directive has driven much research into suitable in vitro alternative assays to support satisfactory risk assessments. One such assay is the reconstructed skin micronucleus (RSMN) assay. First reported in 2006, further development occurred and a standard prot...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/gez037

    authors: Kidd D,Phillips S,Chirom T,Mason N,Smith R,Saul J,Whitwell J,Clements J

    更新日期:2019-12-03 00:00:00

  • Frequency and spectrum of ENU-induced mutation in the Phi X174 transgene in mouse splenic lymphocytes and their significance to spontaneous transgenic rodent mutation frequencies.

    abstract::A perceived disadvantage of transgenic rodent mutation assays is that spontaneous mutant frequencies are high compared to those of endogenous genes and may consequently reduce sensitivity to induced mutation. We have previously argued that unrepaired G:T mismatches from spontaneous deamination of 5-methylcytosine at C...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/gen026

    authors: Valentine CR,Rainey HF,Farrell JM,Shaddock JG,Dobrovolsky VN,Delongchamp RR

    更新日期:2008-09-01 00:00:00

  • How mitochondria record the effects of UV exposure and oxidative stress using human skin as a model tissue.

    abstract::The accumulation of mitochondrial DNA (mtDNA) mutations has been proposed as an underlying cause of the ageing process and mutations have been associated with cancer in many tissues, including human skin. This involvement is linked to the key roles of mitochondrial function and mtDNA in oxidative stress production and...

    journal_title:Mutagenesis

    pub_type: 杂志文章,评审

    doi:10.1093/mutage/gep061

    authors: Birch-Machin MA,Swalwell H

    更新日期:2010-03-01 00:00:00

  • Biodosimetry results obtained by various cytogenetic methods and electron spin resonance spectrometry among inhabitants of a radionuclide contaminated area around the siberian chemical plant (Tomsk-7).

    abstract::On April 6, 1993, near the town of Tomsk (Russia) there was an accident at the Siberian Chemical Plant (SCP) which resulted in extensive contamination of an area of 250 km(2) to the north of SCP with long-lived radionuclides such as (239)Pu, (137)Cs and (90)Sr. Cytogenetic methods and electron spin resonance (ESR) spe...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/14.5.473

    authors: Ilyinskikh NN,Ilyinskikh IN,Porovskiy VA,Natarajan AT,Suskov II,Smirenniy LN,Ilyinskikh EN

    更新日期:1999-09-01 00:00:00

  • Wavelength dependent responses of primary human keratinocytes to combined treatment with benzo[a]pyrene and UV light.

    abstract::The major risk factor for skin cancer is exposure to UV radiation from sunlight, but other environmental exposures may also play a role in combination with UV. We have studied the effects of combined exposure of primary human skin cells in vitro to UVA, UVB or UVC with benzo[a] pyrene (BaP), an environmental carcinoge...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/gei042

    authors: Crallan RA,Ingham E,Routledge MN

    更新日期:2005-07-01 00:00:00

  • Mitotic disturbance by carbaryl and the metabolite 1-naphthol may involve kinase-mediated phosphorylation of 1-naphthol to the protein phosphatase inhibitor 1-naphthylphosphate.

    abstract::Carbaryl causes depolymerization of spindle microtubules and apparent uncoupling of karyokinesis and cytokinesis in mitotic V79 cells. The metabolite 1-naphthol has virtually identical effects at equimolar concentrations. The closely related 2-naphthol causes similar configurations, but at a much lower frequency than ...

    journal_title:Mutagenesis

    pub_type: 杂志文章

    doi:10.1093/mutage/13.4.345

    authors: Renglin A,Olsson A,Wachtmeister CA,Onfelt A

    更新日期:1998-07-01 00:00:00