Peer Review #2 of "The core clock gene Per1 phases molecular and electrical circadian rhythms in SCN neurons (v0.1)"

The safety and efficacy of chemotherapeutics can vary as a function of the time of their delivery during the day. This study aimed to improve the treatment of glioblastoma (GBM), the most common brain cancer, by testing whether the efficacy of the DNA alkylator temozolomide (TMZ) varies with the time of its administration. We found cell-intrinsic, daily rhythms in both human and mouse GBM cells. Circadian time of treatment affected TMZ sensitivity of murine GBM tumor cells in vitro. The maximum TMZ-induced DNA damage response, activation of apoptosis, and growth inhibition occurred near the daily peak in expression of the core clock gene Bmal1. Deletion of Bmal1 (Arntl) abolished circadian rhythms in gene expression and TMZ-induced activation of apoptosis and growth inhibition. These data indicate that tumor cell-intrinsic circadian rhythms are common to GBM tumors and can regulate TMZ cytotoxicity. Optimization of GBM treatment by timing TMZ administration to daily rhythms should be evaluated in prospective clinical trials.

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Response to Comment on “Circadian rhythms in the absence of the clock gene Bmal1”

Science ◽

10.1126/science.abf1930 ◽

2021 ◽

Vol 372 (6539) ◽

pp. eabf1930

Author(s):

Sandipan Ray ◽

Utham K. Valekunja ◽

Alessandra Stangherlin ◽

Steven A. Howell ◽

Ambrosius P. Snijders ◽

...

Keyword(s):

Circadian Rhythms ◽

Skin Fibroblast ◽

Clock Gene ◽

Mouse Skin ◽

Fibroblast Cells ◽

The Core ◽

Core Clock Gene

Ness-Cohn et al. claim that our observations of transcriptional circadian rhythms in the absence of the core clock gene Bmal1 in mouse skin fibroblast cells are supported by inadequate evidence. They claim that they were unable to reproduce some of the original ﬁndings with their reanalysis. We disagree with their analyses and outlook.

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Comment on “Circadian rhythms in the absence of the clock gene Bmal1”

Science ◽

10.1126/science.abe9230 ◽

2021 ◽

Vol 372 (6539) ◽

pp. eabe9230 ◽

Cited By ~ 1

Author(s):

Elan Ness-Cohn ◽

Ravi Allada ◽

Rosemary Braun

Keyword(s):

Circadian Rhythms ◽

Clock Gene ◽

Insufficient Evidence ◽

The Core ◽

Clock Component ◽

Mouse Tissues ◽

Associated Data

Ray et al. (Reports, 14 February 2020, p. 800) report apparent transcriptional circadian rhythms in mouse tissues lacking the core clock component BMAL1. To better understand these surprising results, we reanalyzed the associated data. We were unable to reproduce the original findings, nor could we identify reliably cycling genes. We conclude that there is insufficient evidence to support circadian transcriptional rhythms in the absence of Bmal1.

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Circadian Expression of TIMP3 Is Disrupted by UVB Irradiation and Recovered by Green Tea Extracts

International Journal of Molecular Sciences ◽

10.3390/ijms20040862 ◽

2019 ◽

Vol 20 (4) ◽

pp. 862 ◽

Cited By ~ 1

Author(s):

Sunyoung Park ◽

Eun-Soo Lee ◽

Nok-Hyun Park ◽

Kyeonghwan Hwang ◽

Eun-Gyung Cho

Keyword(s):

Clock Gene ◽

Regulatory Gene ◽

Human Keratinocytes ◽

Ultraviolet B ◽

Rhythmic Expression ◽

The Core ◽

Circadian Expression ◽

Tnf Α ◽

Factor Α ◽

Core Clock Gene

The human skin is the outermost physical barrier and has its own circadian machinery that works either cooperatively with the central clock, or autonomously. Circadian rhythms have been observed in many functions related to epidermal homeostasis including hydration and inflammation, and this functional oscillation is disturbed by ultraviolet radiation (UVR), which is a strong environmental cue. Among the genes estimated to show circadian expression in the skin, metalloproteinase inhibitor 3 (TIMP3), has a rhythmic expression in synchronized human keratinocytes similar to that of the core clock gene PER1 and an epidermal circadian regulatory gene, aquaporin 3 (AQP3) but was antiphase to the core clock gene BMAL1. Tumor necrosis factor-α (TNF-α), the regulatory target of TIMP3 via a disintegrin and metalloproteinase domain 17 (ADAM17), was inversely regulated when TIMP3 expression was downregulated by ultraviolet B (UVB) treatment. When synthetic TIMP3 peptides were applied to the cells, the secretion of TNF-α did not increase following the UVB treatment. Similar to TIMP3 peptides, Camellia sinensis leaf-derived extracts showed a distinguishing efficacy in recovering TIMP3 expression, downregulated by UVB treatment. Together, our results suggest that TIMP3 reversely mediates UVR-induced inflammation by being highly expressed during the daytime; therefore, recovering the circadian expression of TIMP3 using synthetic TIMP3 peptides or bioactive natural ingredients could at least in part inhibit the UVR-induced cellular phenomena.

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Stromal Expression of the Core Clock Gene Period 2 Is Essential for Tumor Initiation and Metastatic Colonization

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.587697 ◽

2020 ◽

Vol 8 ◽

Author(s):

Lee Shaashua ◽

Shimrit Mayer ◽

Chen Lior ◽

Hagar Lavon ◽

Alexander Novoselsky ◽

...

Keyword(s):

Clock Gene ◽

Tumor Initiation ◽

Metastatic Colonization ◽

The Core ◽

Period 2 ◽

Core Clock Gene

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The Adrenal Clock Prevents Aberrant Light-Induced Alterations in Circadian Glucocorticoid Rhythms

Endocrinology ◽

10.1210/en.2018-00769 ◽

2018 ◽

Vol 159 (12) ◽

pp. 3950-3964 ◽

Cited By ~ 11

Author(s):

William C Engeland ◽

Logan Massman ◽

Shubhendu Mishra ◽

J Marina Yoder ◽

Sining Leng ◽

...

Keyword(s):

Molecular Clock ◽

Clock Gene ◽

Cholesterol Metabolism ◽

Ex Vivo ◽

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Targeted Deletion ◽

The Core ◽

Steroidogenic Acute Regulatory ◽

Core Clock Gene

Abstract The glucocorticoid (GC) rhythm is entrained to light-dark (LD) cycles via a molecular clock in the suprachiasmatic nucleus (SCN) and is maintained by an adrenal clock synchronized by SCN-dependent signals. Targeted deletion of the core clock gene Bmal1 can disrupt adrenal clock function. The requirement of the adrenal clock to stabilize the circadian GC rhythm during exposure to aberrant LD cycles was determined using novel aldosterone synthase (AS)Cre/+::Bmal1Fl/Fl mice in which Bmal1 deletion occurred during postnatal adrenal transdifferentiation. To examine whether adrenal Bmal1 deletion results in loss of the adrenal clock, mice were crossed with mPER2::Luciferase (mPER2Luc/+) mice. Adrenals from ASCre/+::Bmal1+/+::PER2Luc/+ [control (CTRL)] mice show mPER2Luc rhythms ex vivo, whereas slices from ASCre/+::Bmal1Fl/Fl::PER2Luc/+ [knockout (KO)] mice show dampened rhythms. To monitor corticosterone rhythmicity, mice were implanted with subcutaneous microdialysis probes and sampled at 60-minute intervals for up to 3 days under 12:12-hour [τ (T) 24] LD or 3.5:3.5-hour (T7) LD cycles. Corticosterone rhythms were entrained to T24 LD in CTRL and KO mice. Under T7 LD, circadian corticosterone rhythms persisted in most CTRL mice but not KO mice. Hyperadrenocorticism also was observed in KO mice under T7 LD, reflected by increased corticosterone peak amplitude, total daily corticosterone, and responses to ACTH. Analysis of dysregulated adrenal genes in KO mice exposed to aberrant light identified candidates involved in cholesterol metabolism and trafficking, including steroidogenic acute regulatory protein, which could increase steroidogenesis. Our results show that the adrenal clock functions to buffer steroidogenic responses to aberrant light and stabilize circadian GC rhythmicity.

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