An Essential and Cell-Cycle-Dependent ORC Dimerization Cycle Regulates Eukaryotic Chromosomal DNA Replication

Abstract

Summary: Eukaryotic DNA replication licensing is a prerequisite for, and plays a role in, regulating genome duplication that occurs exactly once per cell cycle. ORC (origin recognition complex) binds to and marks replication origins throughout the cell cycle and loads other replication-initiation proteins onto replication origins to form pre-replicative complexes (pre-RCs), completing replication licensing. However, how an asymmetric single-heterohexameric ORC structure loads the symmetric MCM (minichromosome maintenance) double hexamers is controversial, and importantly, it remains unknown when and how ORC proteins associate with the newly replicated origins to protect them from invasion by histones. Here, we report an essential and cell-cycle-dependent ORC “dimerization cycle” that plays three fundamental roles in the regulation of DNA replication: providing a symmetric platform to load the symmetric pre-RCs, marking and protecting the nascent sister replication origins for the next licensing, and playing a crucial role to prevent origin re-licensing within the same cell cycle. : Amin et al. provide in vivo evidence for an essential, cell-cycle-dependent, and likely semi-conservative ORC dimerization cycle that regulates eukaryotic chromosomal DNA replication. ORC dimers provide symmetric platforms to load the symmetric pre-RCs at replication origins. ORC de-dimerization produces two single hexamers to bind and protect the two nascent origins. Keywords: DNA replication, replication licensing, pre-RC formation, cell-cycle control, ORC dimerization