The ORC ubiquitin ligase OBI1 promotes DNA replication origin firing

Abstract : DNA replication initiation is a two-step process. During the G1-phase of the cell cycle, the ORC complex, CDC6, CDT1, and MCM2-7 assemble at replication origins, forming pre-replicative complexes (pre-RCs). In S-phase, kinase activities allow fork establishment through (CDC45/MCM2-7/GINS) CMG-complex formation. However, only a subset of all potential origins becomes activated, through a poorly understood selection mechanism. Here we analyse the pre-RC proteomic interactome in human cells and find C13ORF7/RNF219 (hereafter called OBI1, for ORC-ubiquitin-ligase-1) associated with the ORC complex. OBI1 silencing result in defective origin firing, as shown by reduced CMG formation, without affecting pre-RC establishment. OBI1 catalyses the multi-mono-ubiquitylation of a subset of chromatin-bound ORC3 and ORC5 during S-phase. Importantly, expression of non-ubiquitylable ORC3/5 mutants impairs origin firing, demonstrating their relevance as OBI1 substrates for origin firing. Our results identify a ubiquitin signalling pathway involved in origin activation and provide a candidate protein for selecting the origins to be fired.
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Philippe Coulombe, Joelle Nassar, Isabelle Peiffer, Slavica Stanojcic, Yvon Sterkers, et al.. The ORC ubiquitin ligase OBI1 promotes DNA replication origin firing. Nature Communications, Nature Publishing Group, 2019, 10 (1), ⟨10.1038/s41467-019-10321-x⟩. ⟨hal-02408667⟩

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