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Article Dans Une Revue Nature Communications Année : 2019

The ORC ubiquitin ligase OBI1 promotes DNA replication origin firing

Résumé

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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Génétique
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hal-02408667 , version 1 (13-12-2019)

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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, 2019, 10 (1), ⟨10.1038/s41467-019-10321-x⟩. ⟨hal-02408667⟩
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