title: Attenuation of constitutive DNA damage signaling by 1,25-dihydroxyvitamin D3.
abstract: In addition to its traditional role in the regulation of calcium homeostasis and bone metabolism, vitamin D also exhibits immunomodulatory, anti-proliferative and cancer preventive activities. Molecular mechanisms that confer the chemo-preventive properties to vitamin D are poorly understood. We previously reported that constitutive phosphorylation of histone H2AX on Ser139 (γH2AX) and activation of ATM (Ser1981 phosphorylation), seen in untreated normal or tumor cells predominantly in S phase of the cell cycle, is to a large extent indicative of DNA replication stress occurring as a result of persistent DNA damage caused by endogenous oxidants, by-products of oxidative metabolism. In the present study we observed that exposure of mitogenically stimulated human lymphocytes, pulmonary carcinoma A549 and lymphoblastoid TK6 cells to 1,25-dihydroxyvitamin D3 (1,25-VD) reduced the level of constitutive expression of γH2AX and ATM-S1981P. We also observed that the H2O2-induced rise in the level of γH2AX in lymphocytes was attenuated by 1,25-VD. Whereas in lymphocytes 1,25-VD reduced by 50-70% the level of endogenous oxidants as determined by their ability to oxidize 2,7-dichlorodihydrofluorescein (DCFH) in A549 and TK6 cells the attenuation of DNA damage signaling by 1,25-VD was seen in the absence of detectable reduction in DCFH oxidation. These findings suggest that while the anti-oxidant activity of 1,25-VD may contribute to a reduction in the intensity of DNA replication stress in lymphocytes, other factors play a role in the 1,25-VD effects seen in A549 and TK6 cells. The data are consistent with the recent report on the interaction between DNA damage signaling (ATM activation) and 1,25D receptor (VDR) phosphorylation that lead to enhancement of DNA repair efficiency, and provide further support for the chemo-preventive and anti-aging properties of this vitamin/hormone.
authors.affiliation: Brander Cancer Research Institute and Department of Pathology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: H Dorota
authors.initials: HD
authors.lastname: Halicka
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Li
authors.forename: Frank
authors.initials: F
authors.lastname: Traganos
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Darzynkiewicz
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D002117:Calcitriol / Q000235:genetics / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016166:Free Radical Scavengers; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D002117:Calcitriol