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dc.contributor.author
Garcia, Carolina Paola
dc.contributor.author
Videla Richardson, Guillermo
dc.contributor.author
Romorini, Leonardo
dc.contributor.author
Miriuka, Santiago Gabriel
dc.contributor.author
Sevlever, Gustavo
dc.contributor.author
Scassa, Maria Elida
dc.date.available
2018-01-15T18:59:37Z
dc.date.issued
2013-12
dc.identifier.citation
Videla Richardson, Guillermo; Garcia, Carolina Paola; Sevlever, Gustavo; Scassa, Maria Elida; Romorini, Leonardo; Miriuka, Santiago Gabriel; et al.; Topoisomerase I inhibitor, camptothecin, induces apoptogenic signaling in human embryonic stem cells; Elsevier; Stem Cell Research; 12; 2; 12-2013; 400-414
dc.identifier.issn
1873-5061
dc.identifier.uri
http://hdl.handle.net/11336/33303
dc.description.abstract
Embryonic stem cells (ESCs) need to maintain their genomic integrity in response to DNA damage to safeguard the integrity of the organism. DNA double strand breaks (DSBs) are one of the most lethal forms of DNA damage and, if not repaired correctly, they can lead to cell death, genomic instability and cancer. How human ESCs (hESCs) maintain genomic integrity in response to agents that cause DSBs is relatively unclear. In the present study we aim to determine the hESC response to the DSB inducing agent camptothecin (CPT). We find that hESCs are hypersensitive to CPT, as evidenced by high levels of apoptosis. CPT treatment leads to DNA-damage sensor kinase (ATM and DNA-PKcs) phosphorylation on serine 1981 and serine 2056, respectively. Activation of ATM and DNA-PKcs was followed by histone H2AX phosphorylation on Ser 139, a sensitive reporter of DNA damage. Nuclear accumulation and ATM-dependent phosphorylation of p53 on serine 15 were also observed. Remarkably, hESC viability was further decreased when ATM or DNA-PKcs kinase activity was impaired by the use of specific inhibitors. The hypersensitivity to CPT treatment was markedly reduced by blocking p53 translocation to mitochondria with pifithrin-μ. Importantly, programmed cell death was achieved in the absence of the cyclin dependent kinase inhibitor, p21Waf1, a bona fide p53 target gene. Conversely, differentiated hESCs were no longer highly sensitive to CPT. This attenuated apoptotic response was accompanied by changes in cell cycle profile and by the presence of p21Waf1. The results presented here suggest that p53 has a key involvement in preventing the propagation of damaged hESCs when genome is threatened. As a whole, our findings support the concept that the phenomenon of apoptosis is a prominent player in normal embryonic development.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
Human Embryonic Stem Cells
dc.subject
Dna Damage
dc.subject
Apoptosis
dc.subject
Cell Cycle
dc.subject.classification
Otras Ciencias Biológicas
dc.subject.classification
Ciencias Biológicas
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
dc.title
Topoisomerase I inhibitor, camptothecin, induces apoptogenic signaling in human embryonic stem cells
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-01-11T13:49:17Z
dc.journal.volume
12
dc.journal.number
2
dc.journal.pagination
400-414
dc.journal.pais
Países Bajos
dc.journal.ciudad
Ámsterdam
dc.description.fil
Fil: Garcia, Carolina Paola. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Videla Richardson, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina
dc.description.fil
Fil: Romorini, Leonardo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina
dc.description.fil
Fil: Miriuka, Santiago Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina
dc.description.fil
Fil: Sevlever, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina
dc.description.fil
Fil: Scassa, Maria Elida. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina
dc.journal.title
Stem Cell Research
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.scr.2013.12.002
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1873506113001748


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