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
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
3 March 2022
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).
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.
Text
cells-11-00880-v2 (1)
- Version of Record
More information
Accepted/In Press date: 1 March 2022
Published date: 3 March 2022
Additional Information:
Funding Information:
Funding: This research was funded by the University of Latvia Foundation’s PhD Student Scholarship in the Natural and Life Sciences (awarded to N.M.V.), a grant from the European Regional Development Fund (ERDF) projects No. 1.1.1.2/VIAA/3/19/463 for K.S. and ERDF 099 project No. 1.1.1.1/18/A/099) for D.P. and J.E.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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
Catalogue record
Date deposited: 11 May 2022 16:46
Last modified: 06 Jun 2024 01:36
Export record
Altmetrics
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics
