DNA damage and the circadian clock

The circadian transcriptional repressors cryptochrome 1 (Cry1) and 2 (Cry2) evolved from photolyases, bacterial light-activated DNA repair enzymes. In this study, we report that while they have lost DNA repair activity, Cry1/2 adapted to protect genomic integrity by responding to DNA damage through posttranslational modification and coordinating the downstream transcriptional response. We demonstrate that genotoxic stress stimulates Cry1 phosphorylation and its deubiquitination by Herpes virus associated ubiquitin-specific protease (Hausp, a.k.a Usp7), stabilizing Cry1 and shifting circadian clock time. DNA damage also increases Cry2 interaction with Fbxl3, destabilizing Cry2. Thus, genotoxic stress increases the Cry1/Cry2 ratio, suggesting distinct functions for Cry1 and Cry2 following DNA damage. Indeed, the transcriptional response to genotoxic stress is enhanced in Cry1−/− and blunted in Cry2−/− cells. Furthermore, Cry2−/− cells accumulate damaged DNA. These results suggest that Cry1 and Cry2, which evolved from DNA repair enzymes, protect genomic integrity via coordinated transcriptional regulation.

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

10.1101/2022.01.14.476363 ◽

2022 ◽

Author(s):

Ninel Miriam Vainshelbaum ◽

Kristine Salmina ◽

Bogdan I Gerashchenko ◽

Marija Lazovska ◽

Pawel Zayakin ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Circadian Clock ◽

Cancer Cells ◽

Dna Damage Response ◽

Embryonic Stem ◽

Early Embryo ◽

Mitotic Slippage ◽

Damage Response ◽

Telomere Regulation

The Circadian Clock (CC) drives the normal cell cycle and reciprocally regulates telomere elongation. However, it can be deregulated in cancer, embryonic stem cells (ESC) and the early embryo. Here, its role in the resistance of cancer cells to genotoxic treatments was assessed in relation to whole-genome duplication (WGD) and telomere regulation. We first evaluated the DNA damage response of polyploid cancer cells and observed a similar impact on the cell cycle to that seen in ESC - overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, and coupling telomere erosion to accelerated cell senescence, favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Next, we revealed a positive correlation between cancer WGD and deregulation of 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 recombination and return their depolyploidised mitotic offspring to TERT-dependent telomere regulation. Through depolyploidisation and the CC "death loop", the telomeres and Hayflick limit count are thus again renewed. This mechanism along with similar inactivity of the CC in early embryos supports a life-cycle (embryonic) concept of cancer.

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Time-Restricted Feeding Shifts the Skin Circadian Clock and Alters UVB-Induced DNA Damage

Cell Reports ◽

10.1016/j.celrep.2017.07.022 ◽

2017 ◽

Vol 20 (5) ◽

pp. 1061-1072 ◽

Cited By ~ 31

Author(s):

Hong Wang ◽

Elyse van Spyk ◽

Qiang Liu ◽

Mikhail Geyfman ◽

Michael L. Salmans ◽

...

Keyword(s):

Dna Damage ◽

Circadian Clock ◽

Restricted Feeding

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Ticking time bombs: connections between circadian clocks and cancer

F1000Research ◽

10.12688/f1000research.11770.1 ◽

2017 ◽

Vol 6 ◽

pp. 1910 ◽

Cited By ~ 21

Author(s):

Katja A. Lamia

Keyword(s):

Dna Damage ◽

Circadian Clock ◽

Circadian Clocks ◽

Early 20Th Century ◽

Genetic Studies ◽

The Past ◽

Clock Proteins ◽

Increased Risk ◽

Key Players ◽

A Cell

Connections between mammalian circadian and cell division cycles have been postulated since the early 20th century, and epidemiological and genetic studies have linked disruption of circadian clock function to increased risk of several types of cancer. In the past decade, it has become clear that circadian clock components influence cell growth and transformation in a cell-autonomous manner. Furthermore, several molecular mechanistic connections have been described in which clock proteins participate in sensing DNA damage, modulating DNA repair, and influencing the ubiquitination and degradation of key players in oncogenesis (c-MYC) and tumor suppression (p53).

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