TY - JOUR
T1 - Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance
AU - Vainshelbaum, Ninel Miriam
AU - Salmina, Kristine
AU - Gerashchenko, Bogdan I.
AU - Lazovska, Marija
AU - Zayakin, Pawel
AU - Cragg, Mark Steven
AU - Pjanova, Dace
AU - Erenpreisa, Jekaterina
N1 - 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.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
KW - Cancer resistance
KW - Cell cycle
KW - Circadian clock (CC)
KW - DNA damage response (DDR)
KW - Genotoxic treatments
KW - Hayflick limit
KW - Reprogramming
KW - Reversible polyploidy
KW - Senescence
KW - Telomeres
UR - http://www.scopus.com/inward/record.url?scp=85126024402&partnerID=8YFLogxK
U2 - 10.3390/cells11050880
DO - 10.3390/cells11050880
M3 - Article
C2 - 35269502
AN - SCOPUS:85126024402
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 5
M1 - 880
ER -