The ORC ubiquitin ligase OBI1 promotes DNA replication origin firing

Philippe Coulombe (), Joelle Nassar, Isabelle Peiffer, Slavica Stanojcic, Yvon Sterkers, Axel Delamarre, Stéphane Bocquet and Marcel Méchali ()
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Philippe Coulombe: Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier
Joelle Nassar: Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier
Isabelle Peiffer: Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier
Slavica Stanojcic: CNRS 5290 - IRD 224 - University of Montpellier (UMR “MiVEGEC”)
Yvon Sterkers: CNRS 5290 - IRD 224 - University of Montpellier (UMR “MiVEGEC”)
Axel Delamarre: Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier
Stéphane Bocquet: Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier
Marcel Méchali: Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10321-x

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