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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
dc.conicet.fuente individual


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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Atribución-NoComercial-SinDerivadas 2.5 Argentina (CC BY-NC-ND 2.5 AR)