PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors

Autores
Perini, Valentina; Schacke, Michelle; Liddle, Pablo; Vilchez Larrea, Salomé Catalina; Keszenman, Deborah J.; Lafon Hughes, Laura
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes’ assembly. Nuclear PAR affects chromatin’s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polβ), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.
Fil: Perini, Valentina. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Fil: Schacke, Michelle. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Fil: Liddle, Pablo. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Keszenman, Deborah J.. Universidad de la Republica. Centro Universitario del Litoral Norte.; Uruguay
Fil: Lafon Hughes, Laura. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Materia
CDKN2A
KU-0060648
KU55933
OLAPARIB
PARP-1
SCR7 PYRAZINE
VERO CELLS
POLY(ADP-RIBOSYLATION)
RESISTANCE
SYNERGISM
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/127964
Acceder
id CONICETDig_10b2a36e0576e74c9a467c7aaa2e551c
oai_identifier_str oai:ri.conicet.gov.ar:11336/127964
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV InhibitorsPerini, ValentinaSchacke, MichelleLiddle, PabloVilchez Larrea, Salomé CatalinaKeszenman, Deborah J.Lafon Hughes, LauraCDKN2AKU-0060648KU55933OLAPARIBPARP-1SCR7 PYRAZINEVERO CELLSPOLY(ADP-RIBOSYLATION)RESISTANCESYNERGISMhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes’ assembly. Nuclear PAR affects chromatin’s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polβ), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.Fil: Perini, Valentina. Instituto de Investigaciones Biológicas "Clemente Estable"; UruguayFil: Schacke, Michelle. Instituto de Investigaciones Biológicas "Clemente Estable"; UruguayFil: Liddle, Pablo. Instituto de Investigaciones Biológicas "Clemente Estable"; UruguayFil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Keszenman, Deborah J.. Universidad de la Republica. Centro Universitario del Litoral Norte.; UruguayFil: Lafon Hughes, Laura. Instituto de Investigaciones Biológicas "Clemente Estable"; UruguayMDPI AG2020-11-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/127964Perini, Valentina; Schacke, Michelle; Liddle, Pablo; Vilchez Larrea, Salomé Catalina; Keszenman, Deborah J.; et al.; PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors; MDPI AG; International Journal of Molecular Sciences; 21; 21; 5-11-2020; 1-221422-0067CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/21/21/8288info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms21218288info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:01:13Zoai:ri.conicet.gov.ar:11336/127964instacron: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 10:01:13.521CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors
title PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors
spellingShingle PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors
Perini, Valentina
CDKN2A
KU-0060648
KU55933
OLAPARIB
PARP-1
SCR7 PYRAZINE
VERO CELLS
POLY(ADP-RIBOSYLATION)
RESISTANCE
SYNERGISM
title_short PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors
title_full PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors
title_fullStr PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors
title_full_unstemmed PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors
title_sort PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors
dc.creator.none.fl_str_mv Perini, Valentina
Schacke, Michelle
Liddle, Pablo
Vilchez Larrea, Salomé Catalina
Keszenman, Deborah J.
Lafon Hughes, Laura
author Perini, Valentina
author_facet Perini, Valentina
Schacke, Michelle
Liddle, Pablo
Vilchez Larrea, Salomé Catalina
Keszenman, Deborah J.
Lafon Hughes, Laura
author_role author
author2 Schacke, Michelle
Liddle, Pablo
Vilchez Larrea, Salomé Catalina
Keszenman, Deborah J.
Lafon Hughes, Laura
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv CDKN2A
KU-0060648
KU55933
OLAPARIB
PARP-1
SCR7 PYRAZINE
VERO CELLS
POLY(ADP-RIBOSYLATION)
RESISTANCE
SYNERGISM
topic CDKN2A
KU-0060648
KU55933
OLAPARIB
PARP-1
SCR7 PYRAZINE
VERO CELLS
POLY(ADP-RIBOSYLATION)
RESISTANCE
SYNERGISM
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes’ assembly. Nuclear PAR affects chromatin’s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polβ), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.
Fil: Perini, Valentina. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Fil: Schacke, Michelle. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Fil: Liddle, Pablo. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Keszenman, Deborah J.. Universidad de la Republica. Centro Universitario del Litoral Norte.; Uruguay
Fil: Lafon Hughes, Laura. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
description Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes’ assembly. Nuclear PAR affects chromatin’s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polβ), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.
publishDate 2020
dc.date.none.fl_str_mv 2020-11-05
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/11336/127964
Perini, Valentina; Schacke, Michelle; Liddle, Pablo; Vilchez Larrea, Salomé Catalina; Keszenman, Deborah J.; et al.; PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors; MDPI AG; International Journal of Molecular Sciences; 21; 21; 5-11-2020; 1-22
1422-0067
CONICET Digital
CONICET
url http://hdl.handle.net/11336/127964
identifier_str_mv Perini, Valentina; Schacke, Michelle; Liddle, Pablo; Vilchez Larrea, Salomé Catalina; Keszenman, Deborah J.; et al.; PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors; MDPI AG; International Journal of Molecular Sciences; 21; 21; 5-11-2020; 1-22
1422-0067
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.mdpi.com/1422-0067/21/21/8288
info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms21218288
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI AG
publisher.none.fl_str_mv MDPI AG
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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