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A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing.
- Source :
-
Nature communications [Nat Commun] 2013; Vol. 4, pp. 2065. - Publication Year :
- 2013
-
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 Δ(6)PEST, involves a six-amino acid deletion within a previously uncharacterized PEST-like domain. Cdt1 Δ(6)PEST 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.
- Subjects :
- Alleles
Amino Acid Sequence
Animals
Base Sequence
Carcinogenesis
Cell Extracts
Cell Line
Chromatin metabolism
Geminin metabolism
Humans
Mice
Mice, 129 Strain
Mitosis
Models, Biological
Molecular Sequence Data
NIH 3T3 Cells
Phosphorylation
Protein Structure, Tertiary
Sequence Deletion
Ubiquitin-Protein Ligases metabolism
Cell Cycle Proteins chemistry
Cell Cycle Proteins genetics
DNA Replication
DNA-Binding Proteins chemistry
DNA-Binding Proteins genetics
Mutation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 4
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 23817338
- Full Text :
- https://doi.org/10.1038/ncomms3065