Cargando…

p53 downregulates the Fanconi anaemia DNA repair pathway

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 incr...

Descripción completa

Detalles Bibliográficos
Autores principales: Jaber, Sara, Toufektchan, Eléonore, Lejour, Vincent, Bardot, Boris, Toledo, Franck
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821997/
https://www.ncbi.nlm.nih.gov/pubmed/27033104
http://dx.doi.org/10.1038/ncomms11091
_version_ 1782425683526418432
author Jaber, Sara
Toufektchan, Eléonore
Lejour, Vincent
Bardot, Boris
Toledo, Franck
author_facet Jaber, Sara
Toufektchan, Eléonore
Lejour, Vincent
Bardot, Boris
Toledo, Franck
author_sort Jaber, Sara
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4821997
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-48219972016-04-17 p53 downregulates the Fanconi anaemia DNA repair pathway Jaber, Sara Toufektchan, Eléonore Lejour, Vincent Bardot, Boris Toledo, Franck Nat Commun Article 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. Nature Publishing Group 2016-04-01 /pmc/articles/PMC4821997/ /pubmed/27033104 http://dx.doi.org/10.1038/ncomms11091 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Jaber, Sara
Toufektchan, Eléonore
Lejour, Vincent
Bardot, Boris
Toledo, Franck
p53 downregulates the Fanconi anaemia DNA repair pathway
title p53 downregulates the Fanconi anaemia DNA repair pathway
title_full p53 downregulates the Fanconi anaemia DNA repair pathway
title_fullStr p53 downregulates the Fanconi anaemia DNA repair pathway
title_full_unstemmed p53 downregulates the Fanconi anaemia DNA repair pathway
title_short p53 downregulates the Fanconi anaemia DNA repair pathway
title_sort p53 downregulates the fanconi anaemia dna repair pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821997/
https://www.ncbi.nlm.nih.gov/pubmed/27033104
http://dx.doi.org/10.1038/ncomms11091
work_keys_str_mv AT jabersara p53downregulatesthefanconianaemiadnarepairpathway
AT toufektchaneleonore p53downregulatesthefanconianaemiadnarepairpathway
AT lejourvincent p53downregulatesthefanconianaemiadnarepairpathway
AT bardotboris p53downregulatesthefanconianaemiadnarepairpathway
AT toledofranck p53downregulatesthefanconianaemiadnarepairpathway