Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs deficient context
| Autor: | Marcelo de Campos-Nebel, Micaela Palmitelli, Marcela González-Cid |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
G2 Phase
DNA End-Joining Repair CIENCIAS MÉDICAS Y DE LA SALUD DNA damage Context (language use) DNA-Activated Protein Kinase Topoisomerase II poison Biology Histones chemistry.chemical_compound Genetics medicine Mitotic Index Humans DNA Breaks Double-Stranded Homologous Recombination Metaphase Etoposide Chromosome Aberrations Gene Rearrangement MRE11 Homologue Protein Cell growth fungi Bioquímica y Biología Molecular Molecular biology Antineoplastic Agents Phytogenic DNA-Binding Proteins DSB repair pathway enzymes and coenzymes (carbohydrates) Medicina Básica chemistry Cancer research Chromatid Rad51 Recombinase biological phenomena cell phenomena and immunity Homologous recombination Sister Chromatid Exchange G2 phase DNA medicine.drug HeLa Cells Protein Binding |
| DOI: | 10.1007/s10577-015-9478-4 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|