Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA in live cells undergoes continuous oxidative damage caused by metabolically generated endogenous as well as external oxidants and oxidant-inducers. The cumulative oxidative DNA damage is considered the key factor in aging and senescence while the effectiveness of anti-aging agents is often assessed by their ability to reduce such damage. Oxidative DNA damage also preconditions cells to neoplastic transformation. Sensitive reporters of DNA damage, particularly the induction of DNA double-strand breaks (DSBs), are activation of ATM, through its phosphorylation on Ser 1981, and phosphorylation of histone H2AX on Ser 139; the phosphorylated form of H2AX has been named gammaH2AX. We review the observations that constitutive ATM activation (CAA) and H2AX phosphorylation (CHP) take place in normal cells as well in the cells of tumor lines untreated by exogenous genotoxic agents. We postulate that CAA and CHP, which have been measured by multiparameter cytometry in relation to the cell cycle phase, are triggered by oxidative DNA damage. This review also presents the findings on differences in CAA and CHP in various cell lines as well as on the effects of several agents and growth conditions that modulate the extent of these histone and ATM modifications. Specifically, described are effects of the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC), and the glutathione synthetase inhibitor buthionine sulfoximine (BSO) as well as suppression of cell metabolism by growth at higher cell density or in the presence of the glucose antimetabolite 2-deoxy-D-glucose. Collectively, the reviewed data indicate that multiparameter cytometric measurement of the level of CHP and/or CAA allows one to estimate the extent of ongoing oxidative DNA damage and to measure the DNA protective-effects of antioxidants or agents that reduce or amplify generation of endogenous ROS.
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PMID:Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants. 1694 Jul 54

Cepharanthine (CEP), a biscoclaurine (bisbenzylisoquinoline) alkaloid isolated from Stephania cepharantha Hayata, is widely used in Japan to treat variety of diseases. Among a plethora of its biological activities CEP was reported to be able to scavenge radicals and prevent lipid peroxidation. We have recently described the phenomenon of constitutive ATM activation (CAA) and histone H2AX phosphorylation (CHP), the events that report DNA damage induced by endogenously generated radicals, the product of oxidative metabolism in otherwise healthy, untreated cells. The aim of the present study was to explore whether CEP can attenuate the level of CAA and CHP, which would indicate on its ability to protect DNA against endogenous oxidants. The data show that indeed the levels of CAA and CHP in human lymphoblastoid TK6 cells were distinctly lowered upon treatment with CEP. Thus, exposure of cells to 8.3 microM CEP for 4 h led to a reduction of the mean level of CAA and CHP by up to 60% and 50%, respectively. At 1.7 microM CEP the reduction of CAA and CHP after 4 h was 35% and 25%, respectively. Cells exposure to CEP led to a decrease in the level of ondogenous oxidants as measured by the ability to oxidate the fluorescent probe 5-(and-6)-carboxy-2',7'-dichloro-dihydro-fluorescein diacetate. No evidence of apoptosis was seen during the first 8 h of treatment with CEP but initiation of apoptosis (caspase-3 activation) was detected in relatively few (< 10%) cells after exposure to 8.3 microM CEP for 24 h. The data strongly suggest that the scavenging properties of CEP provide a protection of DNA from the radicals generated endogenously during oxidative metabolism.
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PMID:Biscoclaurine alkaloid cepharanthine protects DNA in TK6 lymphoblastoid cells from constitutive oxidative damage. 1827 90