"Mitotic Slippage" and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres.
Kristine SalminaAgnieszka BojkoInna InashkinaKarolina StaniakMagdalena DudkowskaPetar PodlesniyFelikss RumnieksNinel M VainshelbaumDace PjanovaEwa SikoraJekaterina ErenpreisaPublished in: International journal of molecular sciences (2020)
Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of TP53-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-MB-231 cell line treated with doxorubicin (DOX). 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, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle.
Keyphrases
- dna repair
- induced apoptosis
- cell cycle arrest
- mass spectrometry
- dna damage
- multiple sclerosis
- ms ms
- cell cycle
- binding protein
- circulating tumor
- cell free
- cell death
- single molecule
- genome wide
- acute myeloid leukemia
- drug delivery
- gene expression
- life cycle
- small molecule
- endothelial cells
- bone marrow
- young adults
- papillary thyroid
- mesenchymal stem cells
- transcription factor
- high intensity
- smoking cessation
- circulating tumor cells
- replacement therapy
- genome wide identification