Circadian clock genes as modulators of sensitivity to genotoxic stress

Marina P. Antoch, Roman V. Kondratov, Joseph S. Takahashi

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

A broad variety of organisms display circadian rhythms (i.e., oscillations with 24-hr periodicities) in many aspects of their behavior, physiology and metabolism. These rhythms are under genetic control and are generated endogenously at the cellular level. In mammals, the core molecular mechanism of the oscillator consists of two transcriptional activators, CLOCK and BMAL1, and their transcriptional targets, CRYPTOCHROMES (CRYS) and PERIODS (PERS). The CRY and PER proteins function as negative regulators of CLOCK/BMAL1 activity, thus forming the major circadian autoregulatory feedback loop. It is believed that the circadian clock system regulates daily variations in output physiology and metabolism through periodic activation/repression of the set of clock-controlled genes that are involved in various metabolic pathways. Importantly, circadian-controlled pathways include those that determine in vivo responses to genotoxic stress. By using circadian mutant mice deficient in different components of the molecular clock system, we have established genetic models that correlate with the two opposite extremes of circadian cycle as reflected by the activity of the CLOCK/BMAL1 transactivation complex. Comparison of the in vivo responses of these mutants to the chemotherapeutic drug, cyclophosphamide (CY), has established a direct correlation between drug toxicity and the functional status of the CLOCK/BMAL1 transcriptional complex. We have also demonstrated that CLOCK/BMAL1 modulates sensitivity to drug-induced toxicity by controlling B cell responses to active CY metabolites. These results suggest that the sensitivity of cells to genotoxic stress induced by anticancer therapy may be modulated by CLOCK/BMAL1 transcriptional activity. Further elucidation of the molecular mechanisms of circadian control as well as identification of specific pharmacological modulators of CLOCK/BMAL1 activity are likely to lead to the development of new anti-cancer treatment schedules with increased therapeutic index and reduced morbidity.

Original languageEnglish (US)
Pages (from-to)901-907
Number of pages7
JournalCell Cycle
Volume4
Issue number7
StatePublished - Jul 2005

Fingerprint

Circadian Clocks
Drug-Related Side Effects and Adverse Reactions
Cyclophosphamide
Modulators
DNA Damage
Clocks
Genes
Physiology
Metabolism
Toxicity
Genetic Models
Periodicity
Circadian Rhythm
Metabolic Networks and Pathways
Pharmaceutical Preparations
Transcriptional Activation
Mammals
Appointments and Schedules
B-Lymphocytes
Oncology

Keywords

  • Anticancer therapy
  • BMAL1
  • Circadian
  • CLOCK
  • Transcription

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

Circadian clock genes as modulators of sensitivity to genotoxic stress. / Antoch, Marina P.; Kondratov, Roman V.; Takahashi, Joseph S.

In: Cell Cycle, Vol. 4, No. 7, 07.2005, p. 901-907.

Research output: Contribution to journalArticle

Antoch, MP, Kondratov, RV & Takahashi, JS 2005, 'Circadian clock genes as modulators of sensitivity to genotoxic stress', Cell Cycle, vol. 4, no. 7, pp. 901-907.
Antoch, Marina P. ; Kondratov, Roman V. ; Takahashi, Joseph S. / Circadian clock genes as modulators of sensitivity to genotoxic stress. In: Cell Cycle. 2005 ; Vol. 4, No. 7. pp. 901-907.
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