Abstract
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.
Highlights
Once exposed to DNA damaging therapy, tumor cells ( TP53 mutants) undergo a spindle checkpoint arrest, which can be released by mitotic slippage (MS), i.e. mitosis failure and reversal to interphase with a doubled genome [1]
We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase, telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62
Trying to disclose the mechanisms of this incredible resistance, we studied several aspects of the recovery process—reversible polyploidy, reversible senescence, mitotic slippage, repair and sorting of the DNA damage, mechanisms of telomere maintenance, amoeboidization with the change of reproductive modus, and the involved genes—which all converged on telomeres and the atavistic variant of meiosis as a possible novel mechanism of survival escape
Summary
Once exposed to DNA damaging therapy, tumor cells ( TP53 mutants) undergo a spindle checkpoint arrest, which can be released by mitotic slippage (MS), i.e. mitosis failure and reversal to interphase with a doubled genome [1]. Several laboratories independently found that, after passing several such polyploidizing cycles, a proportion of the surviving giant tumor cells undertake the reverse path, depolyploidization, returning “escapers” into the mitotic cycle [2,3,4,5,6,7,8]. The amount of MS is roughly proportional to the drug dosage, it improves cancer cell survival [16]. The mechanisms of this MS-aided cancer resistance, which paradoxically integrates the features of cellular senescence with reprogramming, are poorly understood [8,17,18,19,20,21,22,23,24,25,26,27,28,29]. Extranuclear DNA was reported to be released in senescent cells through the defects or blebs in the nuclear lamina, and digested by lysosomal DNAse II, either directly or via macro-autophagy [35,36,37,38,39,40,41], causing Sting-mediated inflammation and suppression of innate immunity
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