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Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model
The poly (adenosine diphosphate (ADP)-ribosyl) polymerase inhibitors (PARPi) selectively kill cancer cells with BRCA1 or BRCA2 (BRCA)-mutations. It has been proposed that cell death induction after PARPi depends on unrepaired double strand breaks (DSBs) that accumulate due to the homologous recombin...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Sociedade Brasileira de Genética
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198003/ https://www.ncbi.nlm.nih.gov/pubmed/31930278 http://dx.doi.org/10.1590/1678-4685-GMB-2019-0070 |
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author | Paviolo, Natalia Soledad de la Vega, María Belén Pansa, María Florencia García, Iris Alejandra Calzetta, Nicolás Luis Soria, Gastón Gottifredi, Vanesa |
author_facet | Paviolo, Natalia Soledad de la Vega, María Belén Pansa, María Florencia García, Iris Alejandra Calzetta, Nicolás Luis Soria, Gastón Gottifredi, Vanesa |
author_sort | Paviolo, Natalia Soledad |
collection | PubMed |
description | The poly (adenosine diphosphate (ADP)-ribosyl) polymerase inhibitors (PARPi) selectively kill cancer cells with BRCA1 or BRCA2 (BRCA)-mutations. It has been proposed that cell death induction after PARPi depends on unrepaired double strand breaks (DSBs) that accumulate due to the homologous recombination deficiency of BRCA-mutated cells. Such accumulation of DSBs is inferred mainly from the high levels of DNA damage markers like phosphorylated histone H2AX. Herein, we developed a model of isogenic cell lines to show that depletion of BRCA causes PARPi-triggered cell death, replication stress (phosphorylated-H2AX and 53BP1 foci), and genomic instability. However, persistent DSBs accumulation was not detected under the same experimental conditions. Hence, at least in this cellular model, the trigger for cell death in PARPi-treated BRCA-depleted samples is not the accumulation of unrepaired DSBs. Instead, cell death better correlates with a rapid and aberrant resolution of DSBs by error-prone pathways that leads to severe chromosomic aberrations. Therefore, our results suggest that in PARPi-treated BRCA-deficient cells, chromosome aberrations may dually trigger both genomic instability and cell death. |
format | Online Article Text |
id | pubmed-7198003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Sociedade Brasileira de Genética |
record_format | MEDLINE/PubMed |
spelling | pubmed-71980032020-05-08 Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model Paviolo, Natalia Soledad de la Vega, María Belén Pansa, María Florencia García, Iris Alejandra Calzetta, Nicolás Luis Soria, Gastón Gottifredi, Vanesa Genet Mol Biol Articles The poly (adenosine diphosphate (ADP)-ribosyl) polymerase inhibitors (PARPi) selectively kill cancer cells with BRCA1 or BRCA2 (BRCA)-mutations. It has been proposed that cell death induction after PARPi depends on unrepaired double strand breaks (DSBs) that accumulate due to the homologous recombination deficiency of BRCA-mutated cells. Such accumulation of DSBs is inferred mainly from the high levels of DNA damage markers like phosphorylated histone H2AX. Herein, we developed a model of isogenic cell lines to show that depletion of BRCA causes PARPi-triggered cell death, replication stress (phosphorylated-H2AX and 53BP1 foci), and genomic instability. However, persistent DSBs accumulation was not detected under the same experimental conditions. Hence, at least in this cellular model, the trigger for cell death in PARPi-treated BRCA-depleted samples is not the accumulation of unrepaired DSBs. Instead, cell death better correlates with a rapid and aberrant resolution of DSBs by error-prone pathways that leads to severe chromosomic aberrations. Therefore, our results suggest that in PARPi-treated BRCA-deficient cells, chromosome aberrations may dually trigger both genomic instability and cell death. Sociedade Brasileira de Genética 2019-12-13 /pmc/articles/PMC7198003/ /pubmed/31930278 http://dx.doi.org/10.1590/1678-4685-GMB-2019-0070 Text en Copyright © 2019, Sociedade Brasileira de Genética. https://creativecommons.org/licenses/by/4.0/ License information: This is an open-access article distributed under the terms of the Creative Commons Attribution License (type CC-BY), which permits unrestricted use, distribution and reproduction in any medium, provided the original article is properly cited. |
spellingShingle | Articles Paviolo, Natalia Soledad de la Vega, María Belén Pansa, María Florencia García, Iris Alejandra Calzetta, Nicolás Luis Soria, Gastón Gottifredi, Vanesa Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model |
title | Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model |
title_full | Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model |
title_fullStr | Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model |
title_full_unstemmed | Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model |
title_short | Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model |
title_sort | persistent double strand break accumulation does not precede cell death in an olaparib-sensitive brca-deficient colorectal cancer cell model |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198003/ https://www.ncbi.nlm.nih.gov/pubmed/31930278 http://dx.doi.org/10.1590/1678-4685-GMB-2019-0070 |
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