Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Paviolo, Natalia Soledad, de la Vega, María Belén, Pansa, María Florencia, García, Iris Alejandra, Calzetta, Nicolás Luis, Soria, Gastón, Gottifredi, Vanesa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Sociedade Brasileira de Genética 2019
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
_version_ 1783528913840898048
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
work_keys_str_mv AT paviolonataliasoledad persistentdoublestrandbreakaccumulationdoesnotprecedecelldeathinanolaparibsensitivebrcadeficientcolorectalcancercellmodel
AT delavegamariabelen persistentdoublestrandbreakaccumulationdoesnotprecedecelldeathinanolaparibsensitivebrcadeficientcolorectalcancercellmodel
AT pansamariaflorencia persistentdoublestrandbreakaccumulationdoesnotprecedecelldeathinanolaparibsensitivebrcadeficientcolorectalcancercellmodel
AT garciairisalejandra persistentdoublestrandbreakaccumulationdoesnotprecedecelldeathinanolaparibsensitivebrcadeficientcolorectalcancercellmodel
AT calzettanicolasluis persistentdoublestrandbreakaccumulationdoesnotprecedecelldeathinanolaparibsensitivebrcadeficientcolorectalcancercellmodel
AT soriagaston persistentdoublestrandbreakaccumulationdoesnotprecedecelldeathinanolaparibsensitivebrcadeficientcolorectalcancercellmodel
AT gottifredivanesa persistentdoublestrandbreakaccumulationdoesnotprecedecelldeathinanolaparibsensitivebrcadeficientcolorectalcancercellmodel