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SUMMARY The Mre11/Rad50/NBS1 (MRN) complex is thought to be a critical sensor that detects damaged DNA and recruits ATM to DNA foci for activation. However, it remains to be established how the MRN complex regulates ATM recruitment to the DNA foci during DNA double-strand breaks (DSBs). Here we show that Skp2 E3 ligase is a key component for the MRN complex-mediated ATM activation in response to DSBs. Skp2 interacts with NBS1 and triggers K63-linked ubiquitination of NBS1 upon DSBs, which is critical for the interaction of NBS1 with ATM, thereby facilitating ATM recruitment to the DNA foci for activation. Finally, we show that Skp2 deficiency exhibits a defect in homologous recombination (HR) repair, thereby increasing IR sensitivity. Our results provide molecular insights into how Skp2 and the MRN complex coordinate to activate ATM, and identify Skp2-mediatetd NBS1 ubiquitination as a vital event for ATM activation in response to DNA damage.

The industry foundation class ͑IFC͒ standard building model schema is a necessary but not sufficient condition for achieving full interoperability between building information modeling ͑BIM͒ tools. Unless each information exchange within construction project workflows has its specific contents and level of detail defined, the breadth and flexibility of the IFC schema leaves room for errors. The national BIM standard approach for resolving the ambiguities of information exchange is based on "use cases," which precisely define the data required in each information exchange between disciplines in engineering workflows. In this paper, we define specific procedures for developing information delivery manuals ͑IDM͒, which capture the use cases and the precise information to be exchanged. We also identify some of the data semantics we found problematic that require workflow specification. We further propose details of the information capture that allow the IDM to serve as a specification for later implementation and testing. The procedures are illustrated using examples from an IDM specification developed for the domain of architectural precast concrete.