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Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells
In cancer cells, loss of G1/S control is often accompanied by p53 pathway inactivation, the latter usually rationalized as a necessity for suppressing cell cycle arrest and apoptosis. However, we found an unanticipated effect of p53 loss in mouse and human G1-checkpoint-deficient cells: reduction of...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221544/ https://www.ncbi.nlm.nih.gov/pubmed/30322449 http://dx.doi.org/10.7554/eLife.37868 |
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author | Benedict, Bente van Harn, Tanja Dekker, Marleen Hermsen, Simone Kucukosmanoglu, Asli Pieters, Wietske Delzenne-Goette, Elly Dorsman, Josephine C Petermann, Eva Foijer, Floris te Riele, Hein |
author_facet | Benedict, Bente van Harn, Tanja Dekker, Marleen Hermsen, Simone Kucukosmanoglu, Asli Pieters, Wietske Delzenne-Goette, Elly Dorsman, Josephine C Petermann, Eva Foijer, Floris te Riele, Hein |
author_sort | Benedict, Bente |
collection | PubMed |
description | In cancer cells, loss of G1/S control is often accompanied by p53 pathway inactivation, the latter usually rationalized as a necessity for suppressing cell cycle arrest and apoptosis. However, we found an unanticipated effect of p53 loss in mouse and human G1-checkpoint-deficient cells: reduction of DNA damage. We show that abrogation of the G1/S-checkpoint allowed cells to enter S-phase under growth-restricting conditions at the expense of severe replication stress manifesting as decelerated DNA replication, reduced origin firing and accumulation of DNA double-strand breaks. In this system, loss of p53 allowed mitogen-independent proliferation, not by suppressing apoptosis, but rather by restoring origin firing and reducing DNA breakage. Loss of G1/S control also caused DNA damage and activation of p53 in an in vivo retinoblastoma model. Moreover, in a teratoma model, loss of p53 reduced DNA breakage. Thus, loss of p53 may promote growth of incipient cancer cells by reducing replication-stress-induced DNA damage. |
format | Online Article Text |
id | pubmed-6221544 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-62215442018-11-11 Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells Benedict, Bente van Harn, Tanja Dekker, Marleen Hermsen, Simone Kucukosmanoglu, Asli Pieters, Wietske Delzenne-Goette, Elly Dorsman, Josephine C Petermann, Eva Foijer, Floris te Riele, Hein eLife Cancer Biology In cancer cells, loss of G1/S control is often accompanied by p53 pathway inactivation, the latter usually rationalized as a necessity for suppressing cell cycle arrest and apoptosis. However, we found an unanticipated effect of p53 loss in mouse and human G1-checkpoint-deficient cells: reduction of DNA damage. We show that abrogation of the G1/S-checkpoint allowed cells to enter S-phase under growth-restricting conditions at the expense of severe replication stress manifesting as decelerated DNA replication, reduced origin firing and accumulation of DNA double-strand breaks. In this system, loss of p53 allowed mitogen-independent proliferation, not by suppressing apoptosis, but rather by restoring origin firing and reducing DNA breakage. Loss of G1/S control also caused DNA damage and activation of p53 in an in vivo retinoblastoma model. Moreover, in a teratoma model, loss of p53 reduced DNA breakage. Thus, loss of p53 may promote growth of incipient cancer cells by reducing replication-stress-induced DNA damage. eLife Sciences Publications, Ltd 2018-10-16 /pmc/articles/PMC6221544/ /pubmed/30322449 http://dx.doi.org/10.7554/eLife.37868 Text en © 2018, Benedict et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Benedict, Bente van Harn, Tanja Dekker, Marleen Hermsen, Simone Kucukosmanoglu, Asli Pieters, Wietske Delzenne-Goette, Elly Dorsman, Josephine C Petermann, Eva Foijer, Floris te Riele, Hein Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells |
title | Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells |
title_full | Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells |
title_fullStr | Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells |
title_full_unstemmed | Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells |
title_short | Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells |
title_sort | loss of p53 suppresses replication-stress-induced dna breakage in g1/s checkpoint deficient cells |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221544/ https://www.ncbi.nlm.nih.gov/pubmed/30322449 http://dx.doi.org/10.7554/eLife.37868 |
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