Surender Kharbanda

Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit.

The DNA-dependent protein kinase (DNA-PK) controls the repair of double-stranded DNA breaks in mammalian cells. The protein kinase subunit of DNA-PK (DNA-PKcs) is targeted to DNA breaks by association with the Ku DNA-binding heterodimer. Here we show that a Ku association site is present at the carboxyl terminus of DNA-PKcs (amino acids 3002–3850) near the protein kinase domain. Correspondingly, the nuclear c-Abl tyrosine kinase that associates with DNA-PK also binds to the kinase homology domain. The c-Abl SH3 domain binds to amino acids 3414–3850 of DNA-PKcs. c-Abl phosphorylates C-terminal fragments of DNA-PKcs, particularly amino acids 3414–3850. c-Abl phosphorylation of DNA-PKcs disassociates the DNA-PKcs·Ku complex. Thus, Ku and c-Abl provide opposing functions with regard to DNA-PK activity.

Involvement of c-Abl Tyrosine Kinase in Apoptotic Response to Anticancer Agents

The cellular response to anticancer agents that damage DNA includes cell-cycle arrest, activation of DNA repair; and induction of apoptosis. However, the signals that determine cell fate, that is, survival or apoptosis, are largely unknown. The c-Abl tyrosine kinase is activated by diverse types of DNA damage. The available information supports a model in which certain sensors of DNA lesions activate the c-Abl kinase. Other findings support a proapoptotic function for the activated c-Abl kinase that is mediated by at least several downstream effectors known to be associated with the induction of apoptosis.