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Abstract
The DNA-dependent protein kinase (DNA-PK) plays an instrumental role in the overall survival and proliferation of cells. As a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, DNA-PK is best known as a mediator of the cellular response to DNA damage. In this context, DNA-PK has emerged as an intriguing therapeutic target in the treatment of a variety of cancers, especially when used in conjunction with genotoxic chemotherapy or ionizing radiation. Beyond the DNA damage response, DNA-PK activity is necessary for multiple cellular functions, including the regulation of transcription, progression of the cell cycle, and in the maintenance of telomeres. Here, we review what is currently known about DNA-PK regarding its structure and established roles in DNA repair. We also discuss its lesser-known functions, the pharmacotherapies inhibiting its function in DNA repair, and its potential as a therapeutic target in a broader context.
Highlights
The DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase consisting of a catalytic subunit (DNA-PKcs) and a Ku heterodimer that is made up of the Ku70 and Ku80 subunits
DNA-PKcs is instrumental in facilitating telomere end-capping, likely through an interaction with the kinase interacting protein (KIP) and the telomeric repeat-binding factor 2 (TRF2), a subunit of the shelterin complex [67]
DNA-PK has proven to be an intriguing modulator of many cellular functions
Summary
The DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase consisting of a catalytic subunit (DNA-PKcs) and a Ku heterodimer that is made up of the Ku70 and Ku80 subunits. The vWA domain functions as a surface for protein interactions, mediating binding between DNA-PK and factors involved in DNA repair, telomere regulation, and other functions [40]. Before a damage pathway is pursued, a cell must detect the presence of DSBs. H2A histone family member X (H2AX), is phosphorylated both by DNA-PKcs and ATM at its Ser139 residue to form γ-H2AX, a marker of DNA damage, that functions to retain factors involved in DSB repair [12].
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