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The 'ORC cycle': a novel pathway for regulating eukaryotic DNA replication.

Melvin L DePamphilis1

  • 1National Institute of Child Health and Human Development, Building 6/416, 9000 Rockville Pike, National Institutes of Health, Bethesda, MD 20892-2753, USA. depamphm@mail.nih.gov

Gene
|June 13, 2003
PubMed
Summary

The origin recognition complex (ORC) controls DNA replication timing in eukaryotes. Modifications to ORC subunits during the cell cycle ensure replication initiation only occurs in early G1 phase.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The origin recognition complex (ORC) identifies DNA sites for replication initiation.
  • Assembly of pre-replication complexes (pre-RCs) at these sites leads to DNA replication.
  • ORC activity must be regulated to prevent re-replication within a single cell cycle.

Purpose of the Study:

  • To investigate the cell cycle regulation of ORC activity.
  • To understand how ORC function is restricted to the G1 phase.
  • To elucidate the mechanisms that ensure timely DNA replication initiation.

Main Methods:

  • Comparative analysis of ORC regulation across different eukaryotic models (yeast, frog eggs, mammals).
  • Examination of ORC subunit modifications, including phosphorylation and ubiquitination.

Related Experiment Videos

  • Assessment of ORC-chromatin binding dynamics during the cell cycle.

    • Main Results:

    • ORC activity is inhibited during the G1 to S-phase transition through various modification mechanisms.
    • Yeast ORC is phosphorylated by Cdk1/Clb, while frog egg ORC is hyperphosphorylated and released.
    • Mammalian Orc1's chromatin affinity decreases in S-phase, leading to ubiquitination and potential degradation.

    Conclusions:

    • Eukaryotes utilize an 'ORC cycle' to control DNA replication initiation.
    • This cycle restricts pre-RC assembly to the early G1 phase.
    • The ORC cycle is a critical regulatory step determining the onset of DNA replication.