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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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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 |
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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 |
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