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Volume 21
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Article

“Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres

by
Kristine Salmina
1,
Agnieszka Bojko
2,
Inna Inashkina
1,
Karolina Staniak
2,
Magdalena Dudkowska
2,
Petar Podlesniy
3,
Felikss Rumnieks
1,4,
Ninel M Vainshelbaum
1,4,
Dace Pjanova
1,
Ewa Sikora
2 and
Jekaterina Erenpreisa
1,*
1
Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia
2
Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St., 02-093 Warsaw, Poland
3
CiberNed (Centro Investigacion Biomedica en Red Enfermedades Neurodegenerativas), IIBB, Rosello 161, 08036 Barcelona, Spain
4
Faculty of Biology, University of Latvia, LV-1586 Riga, Latvia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(8), 2779; https://doi.org/10.3390/ijms21082779
Submission received: 25 February 2020 / Revised: 13 April 2020 / Accepted: 14 April 2020 / Published: 16 April 2020
(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)
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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.
Keywords: mtTP53 cancer; genotoxic treatment; cellular senescence; polyploidization; extranuclear DNA; amoeboid conversion; ALT; inverted meiosis; budding of mitotic progeny; SQSTM1/p62 mtTP53 cancer; genotoxic treatment; cellular senescence; polyploidization; extranuclear DNA; amoeboid conversion; ALT; inverted meiosis; budding of mitotic progeny; SQSTM1/p62
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MDPI and ACS Style

Salmina, K.; Bojko, A.; Inashkina, I.; Staniak, K.; Dudkowska, M.; Podlesniy, P.; Rumnieks, F.; Vainshelbaum, N.M.; Pjanova, D.; Sikora, E.; et al. “Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres. Int. J. Mol. Sci. 2020, 21, 2779. https://doi.org/10.3390/ijms21082779

AMA Style

Salmina K, Bojko A, Inashkina I, Staniak K, Dudkowska M, Podlesniy P, Rumnieks F, Vainshelbaum NM, Pjanova D, Sikora E, et al. “Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres. International Journal of Molecular Sciences. 2020; 21(8):2779. https://doi.org/10.3390/ijms21082779

Chicago/Turabian Style

Salmina, Kristine, Agnieszka Bojko, Inna Inashkina, Karolina Staniak, Magdalena Dudkowska, Petar Podlesniy, Felikss Rumnieks, Ninel M Vainshelbaum, Dace Pjanova, Ewa Sikora, and et al. 2020. "“Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres" International Journal of Molecular Sciences 21, no. 8: 2779. https://doi.org/10.3390/ijms21082779

APA Style

Salmina, K., Bojko, A., Inashkina, I., Staniak, K., Dudkowska, M., Podlesniy, P., Rumnieks, F., Vainshelbaum, N. M., Pjanova, D., Sikora, E., & Erenpreisa, J. (2020). “Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres. International Journal of Molecular Sciences, 21(8), 2779. https://doi.org/10.3390/ijms21082779

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