Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance

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.

Life Entrapped in a Network of Atavistic Attractors: How to Find a Rescue

“…Results of studies on tumor development published to date (deep sequencing, multi-region sequencing and single-cell sequencing) indicate that a single normal cell is a common origin of cancer [ 60 ]. In order to increase the probability of survival, cancer transformation initiates the creation of multiple clones, along with activation of the ploidy cycle (see Introduction) [ 6 , 61 ]. Transformation also initiates cancer development, which, according to the universal model of cancer transformation and development ( Figure 5 ), occurs as the development of a population of individual cloning cells.…”

“…Cancer is characterized by abundant genetic abnormalities in the form of mutations, single-nucleotide polymorphisms, copy-number alterations, genomic rearrangements and gene fusions [ 76 ]. Moreover, aneuploidy appears early during cancer development and correlates with cancer aggression and resistance to anticancer treatments, favoring cancer progression and poor prognosis [ 6 , 77 , 78 , 79 , 80 , 81 ]. Resistance to anticancer treatments may be related to the possibility of recovering an individual gene’s function by aneuploidy [ 82 , 83 ].…”

“…Today, a lot of cancer theories have been established (for example, more than 20 theories are presented in [ 5 ]), and new theories are introduced all the time, for example, the detached pericyte hypothesis [ 5 ]. Pursuant to another interesting idea, the main driver of cancer development is repeated loss of synchronization between the circadian clock (CC) and the cell cycle [ 6 ]. This loss of synchronization leads to arrest of the mitotic cell cycle, reprogramming, polyploidization and activation of the ploidy cycle [ 6 ].…”

“…Pursuant to another interesting idea, the main driver of cancer development is repeated loss of synchronization between the circadian clock (CC) and the cell cycle [ 6 ]. This loss of synchronization leads to arrest of the mitotic cell cycle, reprogramming, polyploidization and activation of the ploidy cycle [ 6 ]. Then, through depolyploidization, Hayflick’s limit is renewed, cells regain synchronization between CC, and the cell cycle and mitotic cell cycle are activated [ 6 ].…”

“…This loss of synchronization leads to arrest of the mitotic cell cycle, reprogramming, polyploidization and activation of the ploidy cycle [ 6 ]. Then, through depolyploidization, Hayflick’s limit is renewed, cells regain synchronization between CC, and the cell cycle and mitotic cell cycle are activated [ 6 ]. Other studies also indicate the importance of polyploidy during cancer development [ 7 , 8 ].…”