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Role of the circadian clock “Death-Loop” in the DNA damage response underpinning cancer treatment resistance

Role of the circadian clock “Death-Loop” in the DNA damage response underpinning cancer treatment resistance
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. 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; p < 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.

Cancer resistance, Cell cycle, Circadian clock (CC), DNA damage response (DDR), Genotoxic treatments, Hayflick limit, Reprogramming, Reversible polyploidy, Senescence, Telomeres
2073-4409
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c

Cragg, Mark (2022) Role of the circadian clock “Death-Loop” in the DNA damage response underpinning cancer treatment resistance. Cells, 11 (5), [880]. (doi:10.3390/cells11050880).

Record type: Article

Abstract

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; p < 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.

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Accepted/In Press date: 1 March 2022
Published date: 3 March 2022
Keywords: Cancer resistance, Cell cycle, Circadian clock (CC), DNA damage response (DDR), Genotoxic treatments, Hayflick limit, Reprogramming, Reversible polyploidy, Senescence, Telomeres

Identifiers

Local EPrints ID: 456790
URI: http://eprints.soton.ac.uk/id/eprint/456790
ISSN: 2073-4409
PURE UUID: b8c82095-a3cf-4740-92ba-ed9997defb2e
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 11 May 2022 16:46
Last modified: 12 May 2022 01:35

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