Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance
Here, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. Ho...
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MDPI AG
2022-03-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/5/880 |
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| author | Ninel Miriam Vainshelbaum Kristine Salmina Bogdan I. Gerashchenko Marija Lazovska Pawel Zayakin Mark Steven Cragg Dace Pjanova Jekaterina Erenpreisa |
| author_facet | Ninel Miriam Vainshelbaum Kristine Salmina Bogdan I. Gerashchenko Marija Lazovska Pawel Zayakin Mark Steven Cragg Dace Pjanova Jekaterina Erenpreisa |
| author_sort | Ninel Miriam Vainshelbaum |
| collection | DOAJ |
| description | Here, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. However, it is deregulated in embryonic stem cells (ESCs), the early embryo, and cancer. Here, we review the DNA damage response of cancer cells and a similar impact on the cell cycle to that found in ESCs—overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, coupling telomere erosion to accelerated cell senescence, and favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Polyploidy decelerates the CC. We report an intriguing positive correlation between cancer WGD and the deregulation of the CC assessed by bioinformatics on 11 primary cancer datasets (rho = 0.83; <i>p</i> < 0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by ALT-recombination, and return their depolyploidised offspring to telomerase-dependent regulation. By reversing this polyploidy and the CC “death loop”, the mitotic cycle and Hayflick limit count are thus again renewed. Our review and proposed mechanism support a life-cycle concept of cancer and highlight the perspective of cancer treatment by differentiation. |
| first_indexed | 2024-03-09T20:43:21Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T20:43:21Z |
| publishDate | 2022-03-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-03407587bdc04faa94ca37b2842ce2f92023-11-23T22:51:41ZengMDPI AGCells2073-44092022-03-0111588010.3390/cells11050880Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment ResistanceNinel Miriam Vainshelbaum0Kristine Salmina1Bogdan I. Gerashchenko2Marija Lazovska3Pawel Zayakin4Mark Steven Cragg5Dace Pjanova6Jekaterina Erenpreisa7Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, LatviaCancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, LatviaR.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, 03022 Kyiv, UkraineCancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, LatviaCancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, LatviaCentre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UKCancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, LatviaCancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, LatviaHere, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. However, it is deregulated in embryonic stem cells (ESCs), the early embryo, and cancer. Here, we review the DNA damage response of cancer cells and a similar impact on the cell cycle to that found in ESCs—overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, coupling telomere erosion to accelerated cell senescence, and favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Polyploidy decelerates the CC. We report an intriguing positive correlation between cancer WGD and the deregulation of the CC assessed by bioinformatics on 11 primary cancer datasets (rho = 0.83; <i>p</i> < 0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by ALT-recombination, and return their depolyploidised offspring to telomerase-dependent regulation. By reversing this polyploidy and the CC “death loop”, the mitotic cycle and Hayflick limit count are thus again renewed. Our review and proposed mechanism support a life-cycle concept of cancer and highlight the perspective of cancer treatment by differentiation.https://www.mdpi.com/2073-4409/11/5/880cancer resistancegenotoxic treatmentscircadian clock (CC)cell cycleDNA damage response (DDR)reversible polyploidy |
| spellingShingle | Ninel Miriam Vainshelbaum Kristine Salmina Bogdan I. Gerashchenko Marija Lazovska Pawel Zayakin Mark Steven Cragg Dace Pjanova Jekaterina Erenpreisa Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance Cells cancer resistance genotoxic treatments circadian clock (CC) cell cycle DNA damage response (DDR) reversible polyploidy |
| title | Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance |
| title_full | Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance |
| title_fullStr | Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance |
| title_full_unstemmed | Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance |
| title_short | Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance |
| title_sort | role of the circadian clock death loop in the dna damage response underpinning cancer treatment resistance |
| topic | cancer resistance genotoxic treatments circadian clock (CC) cell cycle DNA damage response (DDR) reversible polyploidy |
| url | https://www.mdpi.com/2073-4409/11/5/880 |
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