Activation of recombinational repair in Ewing sarcoma cells carrying EWS-FLI1 fusion gene by chromosome translocation

Chromosome translocation (TL) is an important mode of genomic changes underlying human tumorigenesis, the detailed mechanisms of which are, however, still not well understood. The two major modalities of DNA double strand break repair, i.e. homologous recombination (HR) and non-homologous end-joinin...

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Published in:Scientific reports 2022-08, Vol.12 (1), p.14764-14764, Article 14764
Main Authors: Tanaka, Kazuhiro, Suzuki, Keiji, Miyashita, Kaname, Wakasa, Kentaro, Kawano, Masanori, Nakatsu, Yoshimichi, Tsumura, Hiroshi, Yoshida, Mitsuaki A., Oda, Shinya
Format: Article
Language:English
Subjects:
631/208
631/208/68
Cell fusion
Chromosome translocations
Deoxyribonucleic acid
DNA
DNA damage
DNA microarrays
DNA repair
Ewing's sarcoma
Ewings sarcoma
Fusion protein
Homologous recombination
Humanities and Social Sciences
Irradiation
Mismatch repair
multidisciplinary
Non-homologous end joining
Sarcoma
Science
Science (multidisciplinary)
Sister chromatid exchange
Translocation
Tumor cell lines
Tumorigenesis
Yeast
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Summary:Chromosome translocation (TL) is an important mode of genomic changes underlying human tumorigenesis, the detailed mechanisms of which are, however, still not well understood. The two major modalities of DNA double strand break repair, i.e. homologous recombination (HR) and non-homologous end-joining (NHEJ), have been hypothesized. In a typical TL + human neoplasm, Ewing sarcoma, which is frequently associated with t(11;22) TL encoding the EWS - FLI1 fusion gene, NHEJ has been regarded as a model to explain the disease-specific TL. Using comprehensive microarray approaches, we observed that expression of the HR genes, particularly of RAD51 , is upregulated in TL + Ewing sarcoma cell lines, WE-68 and SK-N-MC, as in the other TL + tumor cell lines and one defective in DNA mismatch repair (MMR). The upregulated RAD51 expression indeed lead to frequent focus formation, which may suggest an activation of the HR pathway in these cells. Furthermore, sister chromatid exchange was frequently observed in the TL + and MMR-defective cells. Intriguingly, ionizing irradiation revealed that the decrease of 53BP1 foci was significantly retarded in the Ewing sarcoma cell lines, suggesting that the NHEJ pathway may be less active in the cells. These observations may support an HR involvement, at least in part, to explain TL in Ewing sarcoma.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-19164-x