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

Philippe Coulombe, Damien Grégoire, Nikolay Tsanov and Marcel Méchali ()
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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
Nikolay Tsanov: Genome Surveillance and Stability Group, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France
Marcel Méchali: Replication and Genome Dynamics Group, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3065

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