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

Cell Rep. 2020 Mar 10;30(10):3323-3338.e6. doi: 10.1016/j.celrep.2020.02.046.

Abstract

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.

Keywords: DNA replication; ORC dimerization; cell-cycle control; pre-RC formation; replication licensing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle*
  • Cell Proliferation
  • Chromatin / metabolism
  • Chromosomes, Fungal / metabolism*
  • DNA Replication*
  • Dimerization*
  • Models, Biological
  • Mutation / genetics
  • Phosphorylation
  • Protein Subunits / metabolism
  • Replication Origin*
  • Saccharomyces cerevisiae / cytology*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism

Substances

  • Chromatin
  • Protein Subunits
  • Saccharomyces cerevisiae Proteins