A Spatial and Functional Interaction of a Heterotetramer Survivin–DNA-PKcs Complex in DNA Damage Response

Abstract Substantial evidence has shown that overexpression of the inhibitor apoptosis protein (IAP) survivin in human tumors correlates significantly with treatment resistance and poor patient prognosis. Survivin serves as a radiation factor impacts DNA damage response by interacting DNA-dependent kinase (DNA-PKcs). However, complexity, molecular determinants, functional consequences this interrelationship remain largely unknown. By applying coimmunoprecipitation flow cytometry-based Förster resonance energy transfer assays, we demonstrated direct involvement baculovirus IAP repeat domain regulation survival repair. This survivin-mediated activity required an interaction residues S20 W67 phosphoinositide 3-kinase (PI3K) DNA-PKcs. In silico docking dynamics simulation analyses, vitro large-scale mass spectrometry suggested heterotetrameric survivin–DNA-PKcs complex results conformational change within DNA-PKcs PI3K domain. Overexpression resulted enhanced enzymatic detection differentially abundant phosphopeptides proteins implicated response. The altered S/T-hydrophobic motif substrate specificity predominant usage S/T-P phosphorylation sites increase substrates including Foxo3. These data demonstrate regulates DNA-PKcs-dependent double-strand break repair via formation complex. Significance: findings provide insight into broaden our knowledge impact modulating cellular See related commentary Iliakis, p. 2270