OBJECTIVES: We recently postulated that constitutive activation of Ataxia Telangiectasia, Mutated (CAA) and constitutive histone H2AX phosphorylation (CHP) seen in cells not treated with genotoxic agents are the events triggered by DNA damage caused by endogenous reactive oxygen species (ROS), the product of mitochondrial oxidative metabolism. The aim of this study was to seek further evidence in support of this postulate, namely to test whether the levels of CAA and CHP correlate with cells metabolic activity. MATERIALS & METHODS: Peripheral blood lymphocytes are non-cycling (G(0)) cells characterized by minimal rate of oxidative metabolism. A dramatic rise in transcriptional and translational activity, an increase in number of mitochondria, and induction of DNA replication, occur during their mitogenic stimulation. This classic model of cell activation was chosen to study a possible correlation between CAA and CHP versus metabolic activity and generation of ROS. RESULTS: The levels of CAA and CHP in lymphocytes were increased many-fold during their stimulation. This increase was paralleled by the rise in extent of endogenously generated ROS. The growth of stimulated lymphocytes in the presence glucose antimetabolite 2-deoxy-D-glucose led to markedly lowered translational activity, decreased ROS generation and correspondingly attenuated CHA and CAA. CONCLUSIONS: The present data are consistent with our postulate that CHP and CAA report DNA damage by endogenous oxidants whose level correlates with metabolic activity. Because cumulative DNA damage by ROS generated via oxidative metabolism is considered the key mechanism responsible for cell ageing and senescence the data imply that these processes are delayed in G(0) quiescent lymphocytes or stem cells as compared with proliferating cells.
OBJECTIVES: We recently postulated that constitutive activation of Ataxia Telangiectasia, Mutated (CAA) and constitutive histone H2AX phosphorylation (CHP) seen in cells not treated with genotoxic agents are the events triggered by DNA damage caused by endogenous reactive oxygen species (ROS), the product of mitochondrial oxidative metabolism. The aim of this study was to seek further evidence in support of this postulate, namely to test whether the levels of CAA and CHP correlate with cells metabolic activity. MATERIALS & METHODS: Peripheral blood lymphocytes are non-cycling (G(0)) cells characterized by minimal rate of oxidative metabolism. A dramatic rise in transcriptional and translational activity, an increase in number of mitochondria, and induction of DNA replication, occur during their mitogenic stimulation. This classic model of cell activation was chosen to study a possible correlation between CAA and CHP versus metabolic activity and generation of ROS. RESULTS: The levels of CAA and CHP in lymphocytes were increased many-fold during their stimulation. This increase was paralleled by the rise in extent of endogenously generated ROS. The growth of stimulated lymphocytes in the presence glucose antimetabolite 2-deoxy-D-glucose led to markedly lowered translational activity, decreased ROS generation and correspondingly attenuated CHA and CAA. CONCLUSIONS: The present data are consistent with our postulate that CHP and CAA report DNA damage by endogenous oxidants whose level correlates with metabolic activity. Because cumulative DNA damage by ROS generated via oxidative metabolism is considered the key mechanism responsible for cell ageing and senescence the data imply that these processes are delayed in G(0) quiescent lymphocytes or stem cells as compared with proliferating cells.
Authors: Toshiki Tanaka; H Dorota Halicka; Xuan Huang; Frank Traganos; Zbigniew Darzynkiewicz Journal: Cell Cycle Date: 2006-09-01 Impact factor: 4.534
Authors: Toshiki Tanaka; Xuan Huang; H Dorota Halicka; Hong Zhao; Frank Traganos; Anthony P Albino; Wei Dai; Zbigniew Darzynkiewicz Journal: Cytometry A Date: 2007-09 Impact factor: 4.355
Authors: Jonathan P McNally; Scott H Millen; Vandana Chaturvedi; Nora Lakes; Catherine E Terrell; Eileen E Elfers; Kaitlin R Carroll; Simon P Hogan; Paul R Andreassen; Julie Kanter; Carl E Allen; Michael M Henry; Jay N Greenberg; Stephan Ladisch; Michelle L Hermiston; Michael Joyce; David A Hildeman; Jonathan D Katz; Michael B Jordan Journal: Proc Natl Acad Sci U S A Date: 2017-05-22 Impact factor: 11.205
Authors: Zbigniew Darzynkiewicz; Frank Traganos; Hong Zhao; H Dorota Halicka; Joanna Skommer; Donald Wlodkowic Journal: Methods Cell Biol Date: 2011 Impact factor: 1.441
Authors: Hong Zhao; H Dorota Halicka; Jiangwei Li; Ewa Biela; Krzysztof Berniak; Jurek Dobrucki; Zbigniew Darzynkiewicz Journal: Cytometry A Date: 2013-09-30 Impact factor: 4.355
Authors: Hong Zhao; Toshiki Tanaka; H Dorota Halicka; Frank Traganos; Miroslaw Zarebski; Jurek Dobrucki; Zbigniew Darzynkiewicz Journal: Cytometry A Date: 2007-11 Impact factor: 4.355
Authors: Tatyana V Pospelova; Zoya N Demidenko; Elena I Bukreeva; Valery A Pospelov; Andrei V Gudkov; Mikhail V Blagosklonny Journal: Cell Cycle Date: 2009-12-01 Impact factor: 4.534