Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model
| Autor: | Nicolás Luis Calzetta, Vanesa Gottifredi, Natalia S. Paviolo, María Florencia Pansa, María Belén de la Vega, Iris Alejandra García, Gastón Soria |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0106 biological sciences
0301 basic medicine Genome instability Programmed cell death endocrine system diseases DNA damage Poly ADP ribose polymerase homologous recombination GAMMAH2AX Biology QH426-470 01 natural sciences ALTERNATIVE END JOINING HOMOLOGOUS RECOMBINATION non-homologous end joining Olaparib PARP 03 medical and health sciences chemistry.chemical_compound NON-HOMOLOGOUS END JOINING purl.org/becyt/ford/3.2 [https] Genetics skin and connective tissue diseases alternative end joining Molecular Biology Articles Non-homologous end joining enzymes and coenzymes (carbohydrates) 030104 developmental biology chemistry Cancer cell Cancer research purl.org/becyt/ford/3 [https] Homologous recombination 010606 plant biology & botany GammaH2AX |
| Zdroj: | Genetics and Molecular Biology, Vol 43, Iss 1 suppl 1 (2019) CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET Genetics and Molecular Biology Genetics and Molecular Biology v.43 n.1 suppl.1 2020 Sociedade Brasileira de Genética (SBG) instacron:SBG |
| ISSN: | 1678-4685 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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