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Chair(s): Syljuåsen, Randi
(SY009) DNA damage: Centrosome separation and cytokinesis.
Muschel, Ruth *,1, 2, Fletcher, Lynda1, Huang, Haomin 1, Zhang, Wei1, Kao, Gary2, Yen, Tim3, 1 Pathology, Philadelphia, PA, USA2 Radiation Oncology, Philadelphia, PA, USA3 Institute for Cancer Research, Philadelphia, PA, USA
ABSTRACT- Activation of the G2/M cell cycle checkpoint by DNA damage prevents cells from entering mitosis. Centrosome separation is initiated in G2 phase and completed in M phase. This critical process for cell division is targeted by the DNA damage checkpoint. Separation of centrosomes is inhibited during a DNA damage induced G2 arrest. The damaged cells fail to activate Nek2, a kinase required for centrosome separation. Failure of Nek2 activity was dependent on ATM and inhibition of Plk1, but was independent of Chk1 and 2 and Cdk1. Inhibition of centrosome separation either by ionizing radiation or by siRNA against Nek2 had an unexpected consequence, that of multinucleate cell formation. Radiated cells after exiting the G2 delay had markedly prolonged cytokinesis also sometimes culminating in formation of multinucleated cells. Their midbodies fail to demonstrate myosin II in contrast to the midbodies of unirradiated cells. These studies define a previously unreported DNA damage response of inhibition of centrosome separation mechanistically linked to Nek2. The defects of cytokinesis and the accumulation of multinucleated cells after radiation may result from and may contribute mechanistically to cell death after radiation..
Key words: checkpoint, centrosome, mitosis, cytokinesis
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