DNA-PK Signaling Pathway

1. DNA-PK Signaling Pathway The DNA-dependent protein kinase (DNA–PK) is a nuclear serine/threonine protein kinase which is activated after the interaction with its target DNA. DNA–PK is a complex composed of a large catalytic subunit named DNA–PKcs and a heterodimer of Ku proteins (Ku70/80) that is a regulatory factor. In many studies, mammalian DNA –PK, as a critical component of the response to DNA damage, has been shown to play an important role in the DNA double-strand break (DSB) repair and recombination. It can cooperate with ATM and ATR to activate related proteins via phosphorylation during the DNA damage response and further processes. In addition, DNA-PK also takes part in the modulation of chromatin structure and the maintenance of telomere. DNA–PKcs is a member of the phosphatidylinositol 3 (PI 3)-kinase family. It is a 470-kD polypeptide with several domains. The 500 residues of DNA – PKcs in carboxyl terminus comprise the highly conserved catalytic kinase domain. There are two domains named FAT and FATC that surround the catalytic domain. They significantly enhance the stabilization of conformational changes to the catalytic core and regulate DNA-PK’s activity. The N-terminal domain is large, mostly containing helical elements and DNA repeats called HEAT, including Huntingtin, Elongation Factor 3, PP2A, and TOR1 repeats as well as groups of phosphorylation sites with important regulatory functions, namely the JK, PQR, and ABCDE phosphorylation clusters. DNA-PKcs is indispensable for the non-homologous end joining (NHEJ) as it induces a conformational change that enables related proteins such as enzymes and factors to access the ends of the double-strand break. It is also required for the unique genetic recombination named V(D)J recombination that utilizes NHEJ to promote immune system diversity during the early stages of T and B cell maturation.