title: RAD18 Is a Maternal Limiting Factor Silencing the UV-Dependent DNA Damage Checkpoint in Xenopus Embryos.
abstract: In early embryos, the DNA damage checkpoint is silent until the midblastula transition (MBT) because of maternal limiting factors of unknown identity. Here we identify the RAD18 ubiquitin ligase as one such factor in Xenopus. We show, in vitro and in vivo, that inactivation of RAD18 function leads to DNA damage-dependent checkpoint activation, monitored by CHK1 phosphorylation. Moreover, we show that the abundance of both RAD18 and PCNA monoubiquitylated (mUb) are developmentally regulated. Increased DNA abundance limits the availability of RAD18 close to the MBT, thereby reducing PCNA(mUb) and inducing checkpoint derepression. Furthermore, we show that this embryonic-like regulation can be reactivated in somatic mammalian cells by ectopic RAD18 expression, therefore conferring resistance to DNA damage. Finally, we find high RAD18 expression in cancer stem cells highly resistant to DNA damage. Together, these data propose RAD18 as a critical embryonic checkpoint-inhibiting factor and suggest that RAD18 deregulation may have unexpected oncogenic potential.
authors.affiliation: Genome Surveillance and Stability Laboratory, CNRS-UPR1142, Institute of Human Genetics, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France.
authors.forename: Chames
authors.initials: C
authors.lastname: Kermi
authors.affiliation: Genome Surveillance and Stability Laboratory, CNRS-UPR1142, Institute of Human Genetics, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France.
authors.forename: Susana
authors.initials: S
authors.lastname: Prieto
authors.affiliation: Genome Surveillance and Stability Laboratory, CNRS-UPR1142, Institute of Human Genetics, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France.
authors.forename: Siem
authors.initials: S
authors.lastname: van der Laan
authors.affiliation: Genome Surveillance and Stability Laboratory, CNRS-UPR1142, Institute of Human Genetics, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Tsanov
authors.affiliation: Genome Surveillance and Stability Laboratory, CNRS-UPR1142, Institute of Human Genetics, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Recolin
authors.affiliation: Laboratoire Universitaire d'Anatomie Pathologique, Faculté de Médecine Rangueil, Université Toulouse III, CHU, INSERM, 1 Avenue Jean Poulhès, CS 53717 Toulouse, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Uro-Coste
authors.affiliation: Laboratoire Universitaire d'Anatomie Pathologique, Faculté de Médecine Rangueil, Université Toulouse III, CHU, INSERM, 1 Avenue Jean Poulhès, CS 53717 Toulouse, France.
authors.forename: Marie-Bernadette
authors.initials: MB
authors.lastname: Delisle
authors.affiliation: Genome Surveillance and Stability Laboratory, CNRS-UPR1142, Institute of Human Genetics, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France. Electronic address: domenico.maiorano@igh.cnrs.fr.
authors.forename: Domenico
authors.initials: D
authors.lastname: Maiorano
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010063:Ovum / Q000166:cytology; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D029867:Xenopus Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology*; D000099270:Y-Family DNA Polymerases
chemical_list: D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D018809:Proliferating Cell Nuclear Antigen; D011494:Protein Kinases; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; D029867:Xenopus Proteins; C000602528:RAD18 protein, Xenopus; C000605867:CHEK1 protein, human; C000605875:Chek1 protein, Xenopus; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases