p53 downregulates the Fanconi anaemia DNA repair pathway

Sara Jaber, Eléonore Toufektchan, Vincent Lejour, Boris Bardot and Franck Toledo ()
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Sara Jaber: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche
Eléonore Toufektchan: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche
Vincent Lejour: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche
Boris Bardot: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche
Franck Toledo: Genetics of Tumour Suppression, Equipe Labellisée Ligue, Institut Curie, Centre de recherche

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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 p53Δ31, a mutant p53 lacking the C terminus, model dyskeratosis congenita. Accordingly, the increased p53 activity in p53Δ31/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, p53Δ31/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.

Date: 2016
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DOI: 10.1038/ncomms11091

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