Involvement of DNA-dependent protein kinase in normal cell cycle progression through mitosis

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) plays an important role in DNA double-strand break (DSB) repair as the underlying mechanism of the non- homologous end joining pathway. When DSBs occur, DNA- PKcs is rapidly phosphorylated at both the Thr-2609 and Ser- 2056 residues, and such phosphorylations are critical for DSB repair. In this study we report that, in addition to responding to DSBs, DNA-PKcs is activated and phosphorylated in normal cell cycle progression through mitosis. Mitotic induction of DNA- PKcs phosphorylation is closely associated with the spindle apparatus at centrosomes and kinetochores. Furthermore, depletion of DNA-PKcs protein levels or inhibition of DNA- PKcs kinase activity results in the delay of mitotic transition because of chromosome misalignment. These results demon- strate for the first time that DNA-PKcs, in addition to its role in DSB repair, is a critical regulator of mitosis and could modulate microtubule dynamics in chromosome segregation