title: p53 downregulates the Fanconi anaemia DNA repair pathway.
abstract: Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes. Mice expressing p53(Δ31), a mutant p53 lacking the C terminus, model dyskeratosis congenita. Accordingly, the increased p53 activity in p53(Δ31/Δ31) fibroblasts correlated with a decreased expression of 4 genes implicated in telomere syndromes. Here we show that these cells exhibit decreased mRNA levels for additional genes contributing to telomere metabolism, but also, surprisingly, for 12 genes mutated in Fanconi anaemia. Furthermore, p53(Δ31/Δ31) fibroblasts exhibit a reduced capacity to repair DNA interstrand crosslinks, a typical feature of Fanconi anaemia cells. Importantly, the p53-dependent downregulation of Fanc genes is largely conserved in human cells. Defective DNA repair is known to activate p53, but our results indicate that, conversely, an increased p53 activity may attenuate the Fanconi anaemia DNA repair pathway, defining a positive regulatory feedback loop.
authors.affiliation: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|CNRS UMR 3244, Paris, France.|PSL Research University, Paris, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Jaber
authors.affiliation: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|CNRS UMR 3244, Paris, France.|PSL Research University, Paris, France.
authors.forename: Eléonore
authors.initials: E
authors.lastname: Toufektchan
authors.affiliation: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|CNRS UMR 3244, Paris, France.|PSL Research University, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lejour
authors.affiliation: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|CNRS UMR 3244, Paris, France.|PSL Research University, Paris, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Bardot
authors.affiliation: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|CNRS UMR 3244, Paris, France.|PSL Research University, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Toledo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004260:DNA Repair; D015536:Down-Regulation; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005199:Fanconi Anemia / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D050704:E2F4 Transcription Factor; C493763:E2f4 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D016159:Tumor Suppressor Protein p53