The Circadian Gene Per1 Plays an Important Role in Cell Growth and DNA Damage Control in Human Cancer Cells

Gery, Sigal; Komatsu, Naoki; Baldjyan, Lilit; Yu, Andrew; Koo, Danielle; Koeffler, H. Phillip

doi:10.1016/j.molcel.2006.03.038

Cited by 513 publications

(568 citation statements)

References 36 publications

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“…It has been shown that two clock proteins, Per1 and Prd4, have integral roles in the ATM-Chk2 DDR pathway 10,11 . Here, we show that HCLK2, an uncharacterized orphan mammalian protein with weak similarity to the C. elegans biological clock protein CLK-2, interacts with components of the S-phase checkpoint and has a critical role in this checkpoint and the subsequent activation of both Fanconi anaemia and homologousrecombination repair responses.…”

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confidence: 99%

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

et al. 2007

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Here, we show that the human homologue of the Caenorhabditis elegans biological clock protein CLK-2 (HCLK2) associates with the S-phase checkpoint components ATR, ATRIP, claspin and Chk1. Consistent with a critical role in the S-phase checkpoint, HCLK2-depleted cells accumulate spontaneous DNA damage in S-phase, exhibit radio-resistant DNA synthesis, are impaired for damage-induced monoubiquitination of FANCD2 and fail to recruit FANCD2 and Rad51 (critical components of the Fanconi anaemia and homologous recombination pathways, respectively) to sites of replication stress. Although Thr 68 phosphorylation of the checkpoint effector kinase Chk2 remains intact in the absence of HCLK2, claspin phosphorylation and degradation of the checkpoint phosphatase Cdc25A are compromised following replication stress as a result of accelerated Chk1 degradation. ATR phosphorylation is known to both activate Chk1 and target it for proteolytic degradation, and depleting ATR or mutation of Chk1 at Ser 345 restored Chk1 protein levels in HCLK2-depleted cells. We conclude that HCLK2 promotes activation of the S-phase checkpoint and downstream repair responses by preventing unscheduled Chk1 degradation by the proteasome.The DNA damage response (DDR) is a complex process involving the orchestration of highly specialized cell-cycle checkpoints that need to be rapidly activated following the detection of damaged DNA. Each of these signalling cascades involves several unique and overlapping factors -classified as sensors, mediators, transducers and effectors -that ultimately lead to the spatio-temporal assembly of multi-protein complexes at the site of damage 1,2 . The functional importance of checkpoints in maintaining genome stability is highlighted by their conservation throughout eukaryotes. As such, defective checkpoint pathways in human cells leads to the accumulation of aberrant DNA and an increased risk of cancer progression, evident from the many human disease syndromes that result from defects in checkpoint factors 3,4 . Therefore, it is important to understand these complex mechanisms at the molecular level to further our knowledge of cancer progression and treatment.Checkpoints operate at the G1-S, S and G2-M boundaries of the cell cycle and are controlled by the ATM-Chk2 and ATR-Chk1 pathways. The S-phase checkpoint, which is under the control of the ATR-Chk1 pathway, has an essential role in maintaining replication-fork integrity during normal S-phase by preventing the collapse of stalled replication forks. The S-phase checkpoint also coordinates cell-cycle arrest and subsequent DNA-repair events when the replication fork encounters DNA damage 5,3,6 . Activation and recruitment of the Fanconi anaemia and homologous recombination-repair pathways to sites of replication stress requires an intact S-phase checkpoint 7 .Recent work in mouse models has highlighted a surprising, yet highly important link between biological clock proteins and the DDR 8,9 . It has been shown that two clock proteins, Per1 and Prd4, have integral roles...

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HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

et al. 2007

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“…25,27) In addition, PER1 interacts with crucial components of cellular stress response pathways including the ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (Chk2) proteins. 28) Accordingly, ectopic expression of PER1 or PER2 results in cell growth inhibition, cell cycle arrest, apoptosis, or loss of clonogenic capacity. [28][29][30] PER1 and PER2 also interact with the androgen receptor (AR) or estrogen receptor (ER), respectively, in that PER1 inhibits AR-dependent transcription and PER2 induces ER degradation.…”

Section: The Physiological Functions Of Core Circa-dian Regulatorsmentioning

confidence: 99%

“…28) Accordingly, ectopic expression of PER1 or PER2 results in cell growth inhibition, cell cycle arrest, apoptosis, or loss of clonogenic capacity. [28][29][30] PER1 and PER2 also interact with the androgen receptor (AR) or estrogen receptor (ER), respectively, in that PER1 inhibits AR-dependent transcription and PER2 induces ER degradation. 31,32) These findings are consistent with the idea that clock proteins act as key players in the cell cycle and DDR by interacting directly with and regulating the functions of the proteins mediating these processes.…”

Section: The Physiological Functions Of Core Circa-dian Regulatorsmentioning

confidence: 99%

A Common Origin: Signaling Similarities in the Regulation of the Circadian Clock and DNA Damage Responses

Uchida

Hirayama

Nishina

2010

Biological & Pharmaceutical Bulletin

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INTRODUCTIONFrom bacteria to humans, almost all organisms can adapt the timing of their physiology to the cyclic changes of their environment, thanks to a naturally-selected intrinsic timekeeping system called the circadian clock. 1) The circadian clock enhances the physiological efficiency and survival of an organism by organizing its behavior and body functions. 2,3) During the circadian day, the organism's physiology is given over to catabolic processes, whereas the anabolic functions of growth, repair and consolidation occur at night. To achieve this schedule in mammals, the circadian clock regulates a number of physiological functions, including sleep and wakefulness, food intake, body temperature, cardiovascular and renal activity, hormone production, hepatic metabolism and immune responses. 4,5) Accordingly, disruption of the circadian clock in humans has been linked to profound effects on health, including insomnia, stomach ailments, depression and cancer. 4,5) In most organisms, the molecular mechanisms underlying the establishment and maintenance of biological rhythms comprise interconnected transcription-translation feedback loops in which some clock factors repress their own transcription once they have attained critical levels. 2,3) These oscillators have the property of being endogenous and cellautonomous systems that maintain their rhythm in the absence of external time cues. 6) Both vertebrates and invertebrates have circadian oscillators scattered throughout their bodies. 7,8) In mammals, the circadian system is composed of both central and peripheral oscillators. 7) The mammalian central clock is located in the suprachiasmatic nucleus (SCN) within the anterior hypothalamus of the brain. 9) This central clock acts as a coordinator and provides time signals via both neural and humoral routes that entrain independent peripheral clocks. Dysfunction of the central clock does not inactivate the peripheral clocks but instead causes individual peripheral oscillators to become temporally uncoupled. [10][11][12] To guarantee that an organism's behavior remains tied to the rhythms of its environment, the circadian clock must be able to reset itself in response to environmental cues. 9,13,14) The main environmental stimulus for organisms is light, which is provided in day-night cycles. Mammals have no photoreceptors in peripheral tissues, 15) so that the effect of light on peripheral clocks is indirect. 13) For the mammalian clock, the SCN integrates photic cues from the retina and uses neural and humoral signals to transmit this information to peripheral clocks, synchronizing them. [16][17][18] This communication between the central and peripheral clocks results in the seamless regulation of fundamental physiological functions. 4,8) Interestingly, peripheral clocks can also respond directly to SCN-independent signals such as feeding and temperature change. 19,20) However, the physiological role of SCN-independent responses of peripheral clocks is not yet fully understood. A recent study has reported that ...

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“…Accelerated tumor development in response to circadian disruption and clock gene deregulation has been recorded. Transcription upregulation of Per1 and Per2 blocks breast-cancer cell proliferation [124] probably by induced cell apoptosis [125]. Per2 has been demonstrated to be a tumor suppressor gene in MCF-7 breast cancer epithelial cells [126] by linking the Estrogenreceptor-α (ER-α) to the circadian system regulating its degradation [127].…”

Section: Circadian Clock and Breast Cancermentioning

confidence: 99%

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

Zubidat

Haim

2017

Journal of Basic and Clinical Physiology and Pharmacology

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Both obesity and breast cancer are already recognized worldwide as the most common syndromes in our modern society. Currently, there is accumulating evidence from epidemiological and experimental studies suggesting that these syndromes are closely associated with circadian disruption. It has been suggested that melatonin (MLT) and the circadian clock genes both play an important role in the development of these syndromes. However, we still poorly understand the molecular mechanism underlying the association between circadian disruption and the modern health syndromes. One promising candidate is epigenetic modifications of various genes, including clock genes, circadian-related genes, oncogenes, and metabolic genes. DNA methylation is the most prominent epigenetic signaling tool for gene expression regulation induced by environmental exposures, such as artificial light-at-night (ALAN). In this review, we first provide an overview on the molecular feedback loops that generate the circadian regulation and how circadian disruption by ALAN can impose adverse impacts on public health, particularly metabolic disorders and breast cancer development. We then focus on the relation between ALAN-induced circadian disruption and both global DNA methylation and specific loci methylation in relation to obesity and breast cancer morbidities. DNA hypo-methylation and DNA hyper-methylation, are suggested as the most studied epigenetic tools for the activation and silencing of genes that regulate metabolic and monostatic responses. Finally, we discuss the potential clinical and therapeutic roles of MLT suppression and DNA methylation patterns as novel biomarkers for the early detection of metabolic disorders and breast cancer development.

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The Circadian Gene Per1 Plays an Important Role in Cell Growth and DNA Damage Control in Human Cancer Cells

Cited by 513 publications

References 36 publications

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

A Common Origin: Signaling Similarities in the Regulation of the Circadian Clock and DNA Damage Responses

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

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