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

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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DNA damage and the circadian clock

Biodiscovery ◽

10.7750/biodiscovery.2014.13.1 ◽

2014 ◽

pp. 1

Author(s):

Stoyan Chakarov ◽

◽

Rumena Petkova ◽

George Russev ◽

Nikolai Zhelev ◽

...

Keyword(s):

Dna Damage ◽

Circadian Clock

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Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans

Nutrients ◽

10.3390/nu11061234 ◽

2019 ◽

Vol 11 (6) ◽

pp. 1234 ◽

Cited By ~ 61

Author(s):

Humaira Jamshed ◽

Robbie Beyl ◽

Deborah Della Manna ◽

Eddy Yang ◽

Eric Ravussin ◽

...

Keyword(s):

Gene Expression ◽

Risk Factors ◽

Circadian Clock ◽

Cardiometabolic Risk ◽

Cardiometabolic Risk Factors ◽

Cardiometabolic Health ◽

Intermittent Fasting ◽

Restricted Feeding ◽

Glucose Levels ◽

Diurnal Patterns

Time-restricted feeding (TRF) is a form of intermittent fasting that involves having a longer daily fasting period. Preliminary studies report that TRF improves cardiometabolic health in rodents and humans. Here, we performed the first study to determine how TRF affects gene expression, circulating hormones, and diurnal patterns in cardiometabolic risk factors in humans. Eleven overweight adults participated in a 4-day randomized crossover study where they ate between 8 am and 2 pm (early TRF (eTRF)) and between 8 am and 8 pm (control schedule). Participants underwent continuous glucose monitoring, and blood was drawn to assess cardiometabolic risk factors, hormones, and gene expression in whole blood cells. Relative to the control schedule, eTRF decreased mean 24-hour glucose levels by 4 ± 1 mg/dl (p = 0.0003) and glycemic excursions by 12 ± 3 mg/dl (p = 0.001). In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene SIRT1 and the autophagy gene LC3A (all p < 0.04), while in the evening, it tended to increase brain-derived neurotropic factor (BNDF; p = 0.10) and also increased the expression of MTOR (p = 0.007), a major nutrient-sensing protein that regulates cell growth. eTRF also altered the diurnal patterns in cortisol and the expression of several circadian clock genes (p < 0.05). eTRF improves 24-hour glucose levels, alters lipid metabolism and circadian clock gene expression, and may also increase autophagy and have anti-aging effects in humans.

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Gene- and tissue-specific alterations of circadian clock gene expression in streptozotocin-induced diabetic mice under restricted feeding

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2004.03.055 ◽

2004 ◽

Vol 317 (2) ◽

pp. 330-334 ◽

Cited By ~ 82

Author(s):

Katsutaka Oishi ◽

Manami Kasamatsu ◽

Norio Ishida

Keyword(s):

Gene Expression ◽

Circadian Clock ◽

Clock Gene ◽

Restricted Feeding ◽

Diabetic Mice ◽

Circadian Clock Gene ◽

Tissue Specific ◽

Clock Gene Expression

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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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Impact of the Circadian Clock on UV-Induced DNA Damage Response and Photocarcinogenesis

Photochemistry and Photobiology ◽

10.1111/php.12662 ◽

2016 ◽

Vol 93 (1) ◽

pp. 296-303 ◽

Cited By ~ 18

Author(s):

Panshak Dakup ◽

Shobhan Gaddameedhi

Keyword(s):

Dna Damage ◽

Circadian Clock ◽

Dna Damage Response ◽

Damage Response

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Enhanced effect of daytime restricted feeding on the circadian rhythm of streptozotocin-induced type 2 diabetic rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00651.2011 ◽

2012 ◽

Vol 302 (9) ◽

pp. E1027-E1035 ◽

Cited By ~ 9

Author(s):

Tao Wu ◽

Fen ZhuGe ◽

Lu Sun ◽

Yinhua Ni ◽

Ou Fu ◽

...

Keyword(s):

Circadian Rhythm ◽

Pineal Gland ◽

Circadian Clock ◽

Clock Genes ◽

Activity Rhythm ◽

Diabetic Rats ◽

Restricted Feeding ◽

Behavioral Rhythm ◽

Type 2 Diabetic

There is increasing awareness of the link between impaired circadian clocks and multiple metabolic diseases. However, the impairment of the circadian clock by type 2 diabetes has not been fully elucidated. To understand whether and how the function of circadian clock is impaired under the diabetic condition, we examined not only the expression of circadian genes in the heart and pineal gland but also the behavioral rhythm of type 2 diabetic and control rats in both the nighttime restricted feeding (NRF) and daytime restricted feeding (DRF) conditions. In the NRF condition, the circadian expression of clock genes in the heart and pineal gland was conserved in the diabetic rats, being similar to that in the control rats. DRF shifted the circadian phases of peripheral clock genes more efficiently in the diabetic rats than those in the control rats. Moreover, the activity rhythm of rats in the diabetic group was completely shifted from the dark phase to the light phase after 5 days of DRF treatment, whereas the activity rhythm of rats in the control group was still under the control of the suprachiasmatic nucleus (SCN) after the same DRF treatment. Furthermore, the serum glucose rhythm of type 2 diabetic rats was also shifted and controlled by the external feeding schedule, ignoring the SCN rhythm. Therefore, DRF shows stronger effect on the reentrainment of circadian rhythm in the type 2 diabetic rats, suggesting that the circadian system in diabetes is unstable and more easily shifted by feeding stimuli.

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