New Players in the Regulation of DNA-PK Activity: Survivin Joins the Crowd
George Iliakis
Abstract
Abstract The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a large protein kinase and a member of the PI3K-related family of protein kinases that also includes ATM and ATR. DNA-PKcs is a unique evolutionary endowment of higher eukaryotes, as it is absent in lower eukaryotes. It is central to the processing of DNA double-strand breaks by classical nonhomologous end-joining, where through interaction with the Ku70/Ku80 heterodimer it generates the DNA-PK holoenzyme. DNA-PK coordinates and regulates the joining of DNA ends through essential structural contributions and by direct phosphorylation of key repair factors, including itself. Recent structural studies advance our understanding of the functions of this giant enzyme and reveal functional complexity and sophistication compatible with a broad spectrum of activities. Along these lines, the observations reported in the article by Güllülü and colleagues in this issue of Cancer Research reveal intriguing new facets in the regulation of DNA-PKcs and open horizons for further exciting research. Güllülü and colleagues found that in addition to known modes of regulation, DNA-PKcs is also regulated by a direct interaction with survivin. The observations expand the functional and regulatory spectrum of this intriguing kinase and suggest contributions to DNA damage response that remain to be characterized. They formed the foundations for the development of drugs disrupting this interaction, thereby potentially sensitizing tumor cells to radiation. See related article by Güllülü et al., p. 2304