ATPase-dependent quality control of DNA replication origin licensing

Nature. 2013 Mar 21;495(7441):339-43. doi: 10.1038/nature11920. Epub 2013 Mar 10.


The regulated loading of the Mcm2-7 DNA helicase (comprising six related subunits, Mcm2 to Mcm7) into pre-replicative complexes at multiple replication origins ensures precise once per cell cycle replication in eukaryotic cells. The origin recognition complex (ORC), Cdc6 and Cdt1 load Mcm2-7 into a double hexamer bound around duplex DNA in an ATP-dependent reaction, but the molecular mechanism of this origin 'licensing' is still poorly understood. Here we show that both Mcm2-7 hexamers in Saccharomyces cerevisiae are recruited to origins by an essential, conserved carboxy-terminal domain of Mcm3 that interacts with and stimulates the ATPase activity of ORC-Cdc6. ATP hydrolysis can promote Mcm2-7 loading, but can also promote Mcm2-7 release if components are missing or if ORC has been inactivated by cyclin-dependent kinase phosphorylation. Our work provides new insights into how origins are licensed and reveals a novel ATPase-dependent mechanism contributing to precise once per cell cycle replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Cell Cycle Proteins / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Replication / genetics*
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Hydrolysis
  • Minichromosome Maintenance Complex Component 3
  • Minichromosome Maintenance Complex Component 7
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Replication Origin / genetics*
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sequence Alignment


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Saccharomyces cerevisiae Proteins
  • TAH11 protein, S cerevisiae
  • Adenosine Triphosphate
  • Adenosine Triphosphatases
  • MCM2 protein, S cerevisiae
  • MCM3 protein, S cerevisiae
  • MCM7 protein, S cerevisiae
  • Minichromosome Maintenance Complex Component 3
  • Minichromosome Maintenance Complex Component 7