title: High Dub3 expression in mouse ESCs couples the G1/S checkpoint to pluripotency.
abstract: The molecular mechanism underlying G1/S checkpoint bypass in mouse embryonic stem cells (ESCs) remains unknown. DNA damage blocks S phase entry by inhibiting the CDK2 kinase through destruction of its activator, the Cdc25A phosphatase. We observed high Cdc25A levels in G1 that persist even after DNA damage in mouse ESCs. We also found higher expression of Dub3, a deubiquitylase that controls Cdc25A protein abundance. Moreover, we demonstrate that the Dub3 gene is a direct target of Esrrb, a key transcription factor of the self-renewal machinery. We show that Dub3 expression is strongly downregulated during neural conversion and precedes Cdc25A destabilization, while forced Dub3 expression in ESCs becomes lethal upon differentiation, concomitant to cell-cycle remodeling and lineage commitment. Finally, knockdown of either Dub3 or Cdc25A induced spontaneous differentiation of ESCs. Altogether, these findings couple the self-renewal machinery to cell-cycle control through a deubiquitylase in ESCs.
authors.affiliation: Genome Surveillance and Stability Laboratory, CNRS-UPR1142, Institute of Human Genetics, 141 Rue de la Cardonille, 34396 Cedex 5, Montpellier, France.
authors.forename: Siem
authors.initials: S
authors.lastname: van der Laan
authors.forename: Nikolay
authors.initials: N
authors.lastname: Tsanov
authors.forename: Carole
authors.initials: C
authors.lastname: Crozet
authors.forename: Domenico
authors.initials: D
authors.lastname: Maiorano
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D010450:Endopeptidases / Q000235:genetics*; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: C098925:Esrrb protein, mouse; D011960:Receptors, Estrogen; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases; D010450:Endopeptidases; C586381:Dub3 protein, mouse; D064570:Ubiquitin-Specific Proteases