Introduction: Mitotic slippage (MS) - mitosis failure and reversal to interphase with a doubled genome , is a typical response of TP53-mutant tumors resistant to genotoxic therapy. MS and associated micronucleation may play a role in escaping cell death via sorting of the intrinsically damaged DNA. The mechanisms of this MS-aided cancer resistance are poorly understood.
Methods: For experimental studies the metastatic triple-negative breast adenocarcinoma MDA-MB-231 cell line, was treated with 100 nM DOX (doxorubicin) for 24 h. After drug removal, cells were sampled over a 3-week period post-treatment until the appearance of escape clones.
Results: After DOX treatment these cells polyploidize, display premature senescence, sort the damaged DNA into the cytoplasm and acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies, where we found colocalization of PML bodies with TRF2, RAD51 and meiotic nuclease SPO11. The cells in repeated MS cycles activate meiotic genes (meiotic recombinase DMC1, meiotic cohesin REC8, meiotic kinase MOS) and display holocentric chromosomes characteristic for inverted meiosis (IM).
Conclusion: Present results investigating the link between DNA damage response, cellular senescence, MS, and the processes of ALT and IM in chemoresistant cancer cells, all converging on telomeres, open a new avenue for further research and possible targeting.
References: Salmina K., et al. “‘Mitotic Slippage’ and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres.” Int. J. Mol. Sci. 2020, 21, 2779.
Acknowledgements: This work was supported by a ERDF project No. 126.96.36.199/VIAA/3/19/463
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