DNA-Dependent protein kinase in DNA damage response: Three decades and beyond

Abstract

Ionizing radiation exerts various biological effects, including cell killing and carcinogenesis, mainly through generating damage on DNA. Among various types of DNA damage, DNA double-strand break (DSB) is considered the most deleterious and most intimately related to biolog?ical effects of radiation. DNA-dependent protein kinase (DNA-PK), consisting of DNA-PK catalytic subunit and Ku80-Ku70 heterodimer (Ku), is activated upon binding to the end of double-stranded DNA and acts as the molecular sensor for DSB. While DSB is repaired mainly through homologous recombination and nonhomologous end joining in eukaryotes, DNA-PK is shown to be essential in the latter pathway. Moreover, DNA-PK is reported to be capable of phosphorylating a number of proteins, suggesting versatile functions of DNA-PK in cellular response to DSB. Here, we review the advance in our understanding on DNA-PK in three decades and remaining problems.