Persistent double strand break accumulation does not precede cell death in an olaparib-sensitive BRCA-deficient colorectal cancer cell model

Autores
Paviolo, Natalia Soledad; de la Vega Páez, María Belén; Pansa, Maria Florencia; García, Iris Alejandra; Calzetta, Nicolás Luis; Soria, Gastón; Gottifredi, Vanesa
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Paviolo, Natalia Soledad. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: de la Vega Páez, María Belén. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pansa, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; Argentina
Fil: García, Iris Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; Argentina
Fil: Calzetta, Nicolás Luis. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Soria, Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina
Fil: Gottifredi, Vanesa. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
ALTERNATIVE END JOINING
GAMMAH2AX
HOMOLOGOUS RECOMBINATION
NON-HOMOLOGOUS END JOINING
PARP
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/130374
Acceder
id CONICETDig_1163eb321a87005fbed443d8013271cd
oai_identifier_str oai:ri.conicet.gov.ar:11336/130374
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Persistent double strand break accumulation does not precede cell death in an olaparib-sensitive BRCA-deficient colorectal cancer cell modelPaviolo, Natalia Soledadde la Vega Páez, María BelénPansa, Maria FlorenciaGarcía, Iris AlejandraCalzetta, Nicolás LuisSoria, GastónGottifredi, VanesaALTERNATIVE END JOININGGAMMAH2AXHOMOLOGOUS RECOMBINATIONNON-HOMOLOGOUS END JOININGPARPhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3The 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.Fil: Paviolo, Natalia Soledad. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: de la Vega Páez, María Belén. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pansa, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: García, Iris Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Calzetta, Nicolás Luis. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Soria, Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; ArgentinaFil: Gottifredi, Vanesa. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaSociedade Brasileira de Genética2019-12-13info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/130374Paviolo, Natalia Soledad; de la Vega Páez, María Belén; Pansa, Maria Florencia; García, Iris Alejandra; Calzetta, Nicolás Luis; et al.; Persistent double strand break accumulation does not precede cell death in an olaparib-sensitive BRCA-deficient colorectal cancer cell model; Sociedade Brasileira de Genética; Genetics and Molecular Biology; 43; 1; 13-12-2019; 1-121415-47571678-4685CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572020000200303&tlng=eninfo:eu-repo/semantics/altIdentifier/doi/10.1590/1678-4685-gmb-2019-0070info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:40:41Zoai:ri.conicet.gov.ar:11336/130374instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:40:41.478CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv 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
spellingShingle Persistent double strand break accumulation does not precede cell death in an olaparib-sensitive BRCA-deficient colorectal cancer cell model
Paviolo, Natalia Soledad
ALTERNATIVE END JOINING
GAMMAH2AX
HOMOLOGOUS RECOMBINATION
NON-HOMOLOGOUS END JOINING
PARP
title_short 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_sort Persistent double strand break accumulation does not precede cell death in an olaparib-sensitive BRCA-deficient colorectal cancer cell model
dc.creator.none.fl_str_mv Paviolo, Natalia Soledad
de la Vega Páez, María Belén
Pansa, Maria Florencia
García, Iris Alejandra
Calzetta, Nicolás Luis
Soria, Gastón
Gottifredi, Vanesa
author Paviolo, Natalia Soledad
author_facet Paviolo, Natalia Soledad
de la Vega Páez, María Belén
Pansa, Maria Florencia
García, Iris Alejandra
Calzetta, Nicolás Luis
Soria, Gastón
Gottifredi, Vanesa
author_role author
author2 de la Vega Páez, María Belén
Pansa, Maria Florencia
García, Iris Alejandra
Calzetta, Nicolás Luis
Soria, Gastón
Gottifredi, Vanesa
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv ALTERNATIVE END JOINING
GAMMAH2AX
HOMOLOGOUS RECOMBINATION
NON-HOMOLOGOUS END JOINING
PARP
topic ALTERNATIVE END JOINING
GAMMAH2AX
HOMOLOGOUS RECOMBINATION
NON-HOMOLOGOUS END JOINING
PARP
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Paviolo, Natalia Soledad. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: de la Vega Páez, María Belén. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pansa, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; Argentina
Fil: García, Iris Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; Argentina
Fil: Calzetta, Nicolás Luis. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Soria, Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina
Fil: Gottifredi, Vanesa. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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.
publishDate 2019
dc.date.none.fl_str_mv 2019-12-13
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/130374
Paviolo, Natalia Soledad; de la Vega Páez, María Belén; Pansa, Maria Florencia; García, Iris Alejandra; Calzetta, Nicolás Luis; et al.; Persistent double strand break accumulation does not precede cell death in an olaparib-sensitive BRCA-deficient colorectal cancer cell model; Sociedade Brasileira de Genética; Genetics and Molecular Biology; 43; 1; 13-12-2019; 1-12
1415-4757
1678-4685
CONICET Digital
CONICET
url http://hdl.handle.net/11336/130374
identifier_str_mv Paviolo, Natalia Soledad; de la Vega Páez, María Belén; Pansa, Maria Florencia; García, Iris Alejandra; Calzetta, Nicolás Luis; et al.; Persistent double strand break accumulation does not precede cell death in an olaparib-sensitive BRCA-deficient colorectal cancer cell model; Sociedade Brasileira de Genética; Genetics and Molecular Biology; 43; 1; 13-12-2019; 1-12
1415-4757
1678-4685
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572020000200303&tlng=en
info:eu-repo/semantics/altIdentifier/doi/10.1590/1678-4685-gmb-2019-0070
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Sociedade Brasileira de Genética
publisher.none.fl_str_mv Sociedade Brasileira de Genética
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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