H2AX phosphorylation as a genotoxicity endpoint

Watters, Gary P.; Smart, Daniel J.; Harvey, James S.; Austin, Caroline A.

doi:10.1016/j.mrgentox.2009.07.007

Cited by 127 publications

(103 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was established recently by different teams that the γ-H2AX assay was more sensitive than the comet test, notably in vivo (Trouiller et al, 2009) but also in vitro (Ismail et al, 2007;Watters et al, 2009;Leopardi et al, 2010). Moreover, this assay was found to be more sensitive than the comet assay when we compare our results regarding PAHs genotoxicity with published data on the same cell line (Plazar et al, 2007;Winter et al, 2008;Tarantini et al, 2009).…”

Section: Genotoxicity Of Pahs In Human Cell Linessupporting

confidence: 54%

“…Nevertheless, the Caco-2 cell line was not suited to our genotoxic assay (Audebert et al, 2010). This new genotoxic assay was based on the detection of the phosphorylation of the histone H2AX (named γH2AX) that reflects a global genotoxic insult resulting from diverse type of DNA damage, notably DNA adducts and oxidative lesions (Zhou et al, 2006;Watters et al, 2009;Audebert et al, 2011;Graillot et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comparative potency approach based on H2AX assay for estimating the genotoxicity of polycyclic aromatic hydrocarbons

Audebert

Zeman

Beaudoin

et al. 2012

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

a b s t r a c t a r t i c l e i n f oPolycyclic Aromatic Hydrocarbons (PAHs) constitute a family of over one hundred compounds and can generally be found in complex mixtures. PAHs metabolites cause DNA damage which can lead to the development of carcinogenesis. Toxicity assessment of PAH complex mixtures is currently expressed in terms of toxic equivalents, based on Toxicity Equivalent Factors (TEFs). However, the definition of new TEFs for a large number of PAH could overcome some limitations of the current method and improve cancer risk assessment. The current investigation aimed at deriving the relative potency factors of PAHs, based on their genotoxic effect measured in vitro and analyzed with mathematical models. For this purpose, we used a new genotoxic assay (γH2AX) with two human cell lines (HepG2 and LS-174T) to analyze the genotoxic properties of 13 selected PAHs at low doses after 24 h treatment. The dose-response for genotoxic effects was modeled with a Hill model; equivalency between PAHs at low dose was assessed by applying constraints to the model parameters. In the two cell lines tested, we observed a clear dose-response for genotoxic effects for 11 tested compounds. LS-174T was on average ten times more sensitive than HepG2 towards PAHs regarding genotoxicity. We developed new TEFs, which we named Genotoxic Equivalent Factor (GEF). Calculated GEF for the tested PAHs were generally higher than the TEF usually used. Our study proposed a new in vitro based method for the establishment of relevant TEFs for PAHs to improve cancer risk assessment.

show abstract

Section: Genotoxicity Of Pahs In Human Cell Linessupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Comparative potency approach based on H2AX assay for estimating the genotoxicity of polycyclic aromatic hydrocarbons

Audebert

Zeman

Beaudoin

et al. 2012

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

show abstract

“…63,66 Furthermore, DSBs are generated in response to genotoxic stress, enabling the use of gH2AX foci as a pharmacodynamic biomarker in the development of anti-cancer drugs and as an indicator of response in patients. 67,68 Foci formation can also potentially act as a relevant biodosimeter for human exposure to IR in cases of unintentional radiation exposure or after radiation therapy in cancer patients. Detection of gH2AX foci is a minimally invasive method that only requires the collection of peripheral blood lymphocytes or skin biopsies.…”

Section: 35mentioning

confidence: 99%

γH2AX: a sensitive molecular marker of DNA damage and repair

2010

View full text Add to dashboard Cite

Phosphorylation of the Ser-139 residue of the histone variant H2AX, forming cH2AX, is an early cellular response to the induction of DNA double-strand breaks. Detection of this phosphorylation event has emerged as a highly specific and sensitive molecular marker for monitoring DNA damage initiation and resolution. Further, analysis of cH2AX foci has numerous other applications including, but not limited to, cancer and aging research. Quantitation of cH2AX foci has also been applied as a useful tool for the evaluation of the efficacy of various developmental drugs, particularly, radiation modifying compounds. This review focuses on the current status of cH2AX as a marker of DNA damage and repair in the context of ionizing radiation. Although the emphasis is on c-radiationinduced cH2AX foci, the effects of other genotoxic insults including exposure to ultraviolet rays, oxidative stress and chemical agents are also discussed.

show abstract

“…Unrepaired or improperly repaired DSBs can lead to chromosomal truncations and translocations, which can contribute to the development of cancer in higher eukaryotic organisms. DSBs are induced following exposure to ionizing radiation as well as treatment with etoposide or bleomycin [19,24,28]. Two major pathways exist in mammalian cells for repair of DNA DSBs: nonhomologous DNA-end-joining (NHEJ) repair and homologous recombination (HR) [9,25].…”

mentioning

confidence: 99%

Establishment of Ku70-Deficient Lung Epithelial Cell Lines and Their Hypersensitivity to Low-Dose X-Irradiation

Koike¹,

Yutoku

Koike

2011

The Journal of Veterinary Medical Science

View full text Add to dashboard Cite

ABSTRACT. In clinical situations, cellular resistance to chemotherapy and radiotherapy is a significant component of tumor treatment failure. The DNA repair protein Ku70 is a key contributor to chemoresistance to anticancer agents, e.g., etoposide and bleomycin, or radioresistance. Ku70 plays a key role as a sensor of DNA double-strand breaks (DSBs) induced following exposure to ionizing radiation as well as treatment with some chemotherapeutic drugs. The responses of different organs to radiation vary widely and likely depend on the cell population in the organs. However, it is not clear whether Ku70 plays a role in the low-dose radioresistance of lung epithelial cells. In this study, we established Ku70-deficient epithelial cell lines from murine lungs lacking Ku70. Ku70-/-lung epithelial cells exhibited reduced Ku80 expression. Moreover, Ku70-/-lung epithelial cells were more sensitive than controls (Ku70+/-lung epithelial cells) to low-dose X-irradiation (< 0.5 Gy). We also found that consistent with the Ku70 function as a sensor of DSBs, Ku70 mainly localized in the nuclei of murine lung epithelial cells. These findings clearly indicate that Ku70 plays a key role in regulation of the Ku80 expression level in and the radioresistance of lung epithelial cells. Our data also suggest that these cell lines might be useful not only for study of Ku70 functions and the DSB repair pathway, but also for study of the molecular mechanism underlying the sensitivity to chemotherapeutic drugs and radiation in lung epithelial cells.

show abstract

H2AX phosphorylation as a genotoxicity endpoint

Cited by 127 publications

References 59 publications

Comparative potency approach based on H2AX assay for estimating the genotoxicity of polycyclic aromatic hydrocarbons

Comparative potency approach based on H2AX assay for estimating the genotoxicity of polycyclic aromatic hydrocarbons

γH2AX: a sensitive molecular marker of DNA damage and repair

Establishment of Ku70-Deficient Lung Epithelial Cell Lines and Their Hypersensitivity to Low-Dose X-Irradiation

Contact Info

Product

Resources

About