Abstract
Filamin-A (filamin-1) is an actin-binding protein involved in the organization of actin networks. Our previous study shows that filamin-A interacts with BRCA2, and lack of filamin-A expression results in increased cellular sensitivity to several DNA damaging agents in melanoma cells (Yuan, Y., and Shen, Z. (2001) J. Biol. Chem. 276, 48318-48324), suggesting a role of filamin-A in DNA damage response. In this report, we demonstrated that deficiency of filamin-A results in an 8-h delay in the recovery from G2 arrest in response to ionizing radiation. However, filamin-A deficiency does not affect the initial activation of the G2/M checkpoint. We also found that filamin-A deficiency results in sustained activation of Chk1 and Chk2 after irradiation. This in turn causes a delay in the dephosphorylation of phospho-Cdc2, which is inhibitory to the G2/M transition. In addition, filamin-A-deficient M2 cells undergo mitotic catastrophe-related nuclear fragmentation after they are released from the G2 arrest. Together, these data suggest a functional role of filamin-A in the recovery from G2 arrest and subsequent mitotic cell death after DNA damage.
Highlights
In response to DNA damage, cell cycle checkpoints are activated to delay or block the progression of the cell cycle
The activation of cell cycle checkpoints plays a significant role in the DNA damage response
Much is known about the genes that activate the G2/M checkpoint, little is known about the genes that control the recovery from G2 arrest in mammalian cells
Summary
In response to DNA damage, cell cycle checkpoints are activated to delay or block the progression of the cell cycle. These data suggest a functional role of filamin-A in the recovery from G2 arrest and subsequent mitotic cell death after DNA damage. These data provide the first evidence that filamin-A plays a significant role in the recovery from radiation-induced G2 arrest and mitotic cell death in mammalian cells.
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