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A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing

Author

Listed:
  • Philippe Coulombe

    (Replication and Genome Dynamics Group, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France)

  • Damien Grégoire

    (Replication and Genome Dynamics Group, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France
    Present address: Montpellier Institute of Molecular Genetics, CNRS, 1919 Route de Mende, 34293 Montpellier Cedex 5, France)

  • Nikolay Tsanov

    (Genome Surveillance and Stability Group, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France
    Present address: Montpellier Institute of Molecular Genetics, CNRS, 1919 Route de Mende, 34293 Montpellier Cedex 5, France)

  • Marcel Méchali

    (Replication and Genome Dynamics Group, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France)

Abstract

Cdt1 is required for loading the replicative DNA helicase MCM2/7, a process known as DNA replication licensing. Here we show that 129 mouse strains express a Cdt1 mutated allele with enhanced licensing activity. The mutation, named Δ6PEST, involves a six-amino acid deletion within a previously uncharacterized PEST-like domain. Cdt1 Δ6PEST and more extensive deletions exhibit increased re-replication and transformation activities that are independent of the Geminin and E3 ligase pathways. This PEST domain negatively regulates cell cycle-dependent chromatin recruitment of Cdt1 in G2/M phases of the cell cycle. Mass spectrometry analysis indicates that Cdt1 is phosphorylated at sites within the deleted PEST domain during mitosis. This study reveals a conserved new regulatory Cdt1 domain crucial for proper DNA licensing activity and suggests a mechanism by which the presence of Cdt1 in G2/M phases does not lead to premature origin licensing. These results also question the usage of 129 mouse strains for knockout analyses.

Suggested Citation

  • Philippe Coulombe & Damien Grégoire & Nikolay Tsanov & Marcel Méchali, 2013. "A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing," Nature Communications, Nature, vol. 4(1), pages 1-10, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3065
    DOI: 10.1038/ncomms3065
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