Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context

Autores
Palmitelli, Micaela; de Campos Nebel, Ildefonso Marcelo; Gonzalez Cid, Marcela Beatriz
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Etoposide (ETO), a drug used for the treatment of human tumors, is associated with the development of secondary malignancies. Recently, therapeutic strategies have incorporated chemosensitizing agents to improve the tumoral response to this drug. ETO creates DNA double strand breaks (DSB) via inhibition of DNA Topoisomerase II (Top2). To repair DSB, homologous recombination (HR) and non-homologous end-joining (NHEJ), involving D-NHEJ (dependent of DNA-PKcs) and B-NHEJ (backup repair pathway) are activated. We evaluated the progression of the DNA damage induced by the Top2 poison ETO in G2 HeLa human cells after chemical inhibition of DNA-PKcs. The inhibition by NU7026 together with ETO treatment resulted in a 2-fold higher rate of chromatid breaks and exchanges compared to ETO alone. Moreover, it was shown an increment in the percentage of micronuclei with H2AX positive signals in binucleated cells and a slight increase of dicentric chromosomes on second metaphases. It was also observed that in post-mitotic G1 phase, there is a closely association between unresolved DSB and MRE11 (Meiotic Recombination 11 homolog A) signals, demonstrating the contribution of MRE11 in the DSB repair by B-NHEJ. DNA-PKcs chemical inhibition impaired both D-NHEJ and HR repair pathways, altering the maintenance of chromosomal integrity and the cellular proliferative capacity. Thus, our results suggest that the chemosensitizing effectiveness of the DNA-PKcs inhibitor and the survival rate of aberrant cells may be determinants in the development of therapy-related tumors.
Fil: Palmitelli, Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: de Campos Nebel, Ildefonso Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Gonzalez Cid, Marcela Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Materia
Topoisomerase Ii Poison
Dna Damage
Dsb Repair Pathway
G2 Phase
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:11336/42753
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient contextPalmitelli, Micaelade Campos Nebel, Ildefonso MarceloGonzalez Cid, Marcela BeatrizTopoisomerase Ii PoisonDna DamageDsb Repair PathwayG2 Phasehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Etoposide (ETO), a drug used for the treatment of human tumors, is associated with the development of secondary malignancies. Recently, therapeutic strategies have incorporated chemosensitizing agents to improve the tumoral response to this drug. ETO creates DNA double strand breaks (DSB) via inhibition of DNA Topoisomerase II (Top2). To repair DSB, homologous recombination (HR) and non-homologous end-joining (NHEJ), involving D-NHEJ (dependent of DNA-PKcs) and B-NHEJ (backup repair pathway) are activated. We evaluated the progression of the DNA damage induced by the Top2 poison ETO in G2 HeLa human cells after chemical inhibition of DNA-PKcs. The inhibition by NU7026 together with ETO treatment resulted in a 2-fold higher rate of chromatid breaks and exchanges compared to ETO alone. Moreover, it was shown an increment in the percentage of micronuclei with H2AX positive signals in binucleated cells and a slight increase of dicentric chromosomes on second metaphases. It was also observed that in post-mitotic G1 phase, there is a closely association between unresolved DSB and MRE11 (Meiotic Recombination 11 homolog A) signals, demonstrating the contribution of MRE11 in the DSB repair by B-NHEJ. DNA-PKcs chemical inhibition impaired both D-NHEJ and HR repair pathways, altering the maintenance of chromosomal integrity and the cellular proliferative capacity. Thus, our results suggest that the chemosensitizing effectiveness of the DNA-PKcs inhibitor and the survival rate of aberrant cells may be determinants in the development of therapy-related tumors.Fil: Palmitelli, Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: de Campos Nebel, Ildefonso Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gonzalez Cid, Marcela Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaSpringer2015-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/42753Palmitelli, Micaela; de Campos Nebel, Ildefonso Marcelo; Gonzalez Cid, Marcela Beatriz; Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context; Springer; Chromosome Research; 23; 4; 12-2015; 719-7320967-38491573-6849CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007%2Fs10577-015-9478-4info:eu-repo/semantics/altIdentifier/doi/10.1007/s10577-015-9478-4info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:56:54Zoai:ri.conicet.gov.ar:11336/42753instacron: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 09:56:55.048CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context
title Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context
spellingShingle Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context
Palmitelli, Micaela
Topoisomerase Ii Poison
Dna Damage
Dsb Repair Pathway
G2 Phase
title_short Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context
title_full Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context
title_fullStr Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context
title_full_unstemmed Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context
title_sort Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context
dc.creator.none.fl_str_mv Palmitelli, Micaela
de Campos Nebel, Ildefonso Marcelo
Gonzalez Cid, Marcela Beatriz
author Palmitelli, Micaela
author_facet Palmitelli, Micaela
de Campos Nebel, Ildefonso Marcelo
Gonzalez Cid, Marcela Beatriz
author_role author
author2 de Campos Nebel, Ildefonso Marcelo
Gonzalez Cid, Marcela Beatriz
author2_role author
author
dc.subject.none.fl_str_mv Topoisomerase Ii Poison
Dna Damage
Dsb Repair Pathway
G2 Phase
topic Topoisomerase Ii Poison
Dna Damage
Dsb Repair Pathway
G2 Phase
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Etoposide (ETO), a drug used for the treatment of human tumors, is associated with the development of secondary malignancies. Recently, therapeutic strategies have incorporated chemosensitizing agents to improve the tumoral response to this drug. ETO creates DNA double strand breaks (DSB) via inhibition of DNA Topoisomerase II (Top2). To repair DSB, homologous recombination (HR) and non-homologous end-joining (NHEJ), involving D-NHEJ (dependent of DNA-PKcs) and B-NHEJ (backup repair pathway) are activated. We evaluated the progression of the DNA damage induced by the Top2 poison ETO in G2 HeLa human cells after chemical inhibition of DNA-PKcs. The inhibition by NU7026 together with ETO treatment resulted in a 2-fold higher rate of chromatid breaks and exchanges compared to ETO alone. Moreover, it was shown an increment in the percentage of micronuclei with H2AX positive signals in binucleated cells and a slight increase of dicentric chromosomes on second metaphases. It was also observed that in post-mitotic G1 phase, there is a closely association between unresolved DSB and MRE11 (Meiotic Recombination 11 homolog A) signals, demonstrating the contribution of MRE11 in the DSB repair by B-NHEJ. DNA-PKcs chemical inhibition impaired both D-NHEJ and HR repair pathways, altering the maintenance of chromosomal integrity and the cellular proliferative capacity. Thus, our results suggest that the chemosensitizing effectiveness of the DNA-PKcs inhibitor and the survival rate of aberrant cells may be determinants in the development of therapy-related tumors.
Fil: Palmitelli, Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: de Campos Nebel, Ildefonso Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Gonzalez Cid, Marcela Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
description Etoposide (ETO), a drug used for the treatment of human tumors, is associated with the development of secondary malignancies. Recently, therapeutic strategies have incorporated chemosensitizing agents to improve the tumoral response to this drug. ETO creates DNA double strand breaks (DSB) via inhibition of DNA Topoisomerase II (Top2). To repair DSB, homologous recombination (HR) and non-homologous end-joining (NHEJ), involving D-NHEJ (dependent of DNA-PKcs) and B-NHEJ (backup repair pathway) are activated. We evaluated the progression of the DNA damage induced by the Top2 poison ETO in G2 HeLa human cells after chemical inhibition of DNA-PKcs. The inhibition by NU7026 together with ETO treatment resulted in a 2-fold higher rate of chromatid breaks and exchanges compared to ETO alone. Moreover, it was shown an increment in the percentage of micronuclei with H2AX positive signals in binucleated cells and a slight increase of dicentric chromosomes on second metaphases. It was also observed that in post-mitotic G1 phase, there is a closely association between unresolved DSB and MRE11 (Meiotic Recombination 11 homolog A) signals, demonstrating the contribution of MRE11 in the DSB repair by B-NHEJ. DNA-PKcs chemical inhibition impaired both D-NHEJ and HR repair pathways, altering the maintenance of chromosomal integrity and the cellular proliferative capacity. Thus, our results suggest that the chemosensitizing effectiveness of the DNA-PKcs inhibitor and the survival rate of aberrant cells may be determinants in the development of therapy-related tumors.
publishDate 2015
dc.date.none.fl_str_mv 2015-12
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/11336/42753
Palmitelli, Micaela; de Campos Nebel, Ildefonso Marcelo; Gonzalez Cid, Marcela Beatriz; Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context; Springer; Chromosome Research; 23; 4; 12-2015; 719-732
0967-3849
1573-6849
CONICET Digital
CONICET
url http://hdl.handle.net/11336/42753
identifier_str_mv Palmitelli, Micaela; de Campos Nebel, Ildefonso Marcelo; Gonzalez Cid, Marcela Beatriz; Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context; Springer; Chromosome Research; 23; 4; 12-2015; 719-732
0967-3849
1573-6849
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://link.springer.com/article/10.1007%2Fs10577-015-9478-4
info:eu-repo/semantics/altIdentifier/doi/10.1007/s10577-015-9478-4
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
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
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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