Oncogenes and Circadian Clock

*Oncogenes and Carcinogenesis*

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**Chapter 2**

**Abstract**

**1. Introduction**

Activation

A Molecular Link between the

Circadian Clock, DNA Damage

*Yoshimi Okamoto-Uchida, Junko Izawa and Jun Hirayama*

Circadian clocks enhance the efficiency and survival of living things by organizing their behavior and body functions. There has been a long history of research seeking a link between circadian clock and tumorigenesis. Studies of animal models and human tumor samples have revealed that the dysregulation of circadian clocks is an important endogenous factor causing mammalian cancer development. The core circadian clock regulators have been implicated in the control of both the cell cycle and DNA damage responses (DDR). Conversely, several intracellular signaling cascades that play important roles in regulation of the cell cycle and the DDR also contribute to circadian clock regulation. This review describes selected regulatory aspects of circadian clocks, providing evidence of a

**Keywords:** circadian clock, DNA damage response, DNA repair, oncogenes

Circadian (derived from Latin "around the day") clocks constitute ubiquitous processes that regulate various biochemical and physiological events occurring with a 24 h periodicity, even in the absence of external cues [1, 2]. Under natural conditions, clocks are entrained to a 24 h day by environmental time cues, most commonly light. Circadian clocks are established in cell-autonomous oscillators, referred to as cellular clocks, which are controlled by a transcription/translationbased negative feedback loop [3, 4]. In humans, the circadian clock generates circadian rhythms in synthesis and release of hormones and cardiovascular activities such as heart rate, blood pressure, and vascular tone [5, 6]. Moreover, immune responses show temporal changes in antibody levels and total number of lymphocytes, which are related to circadian variations [7]. Therefore, dysfunction of the clock can cause a variety of diseases. In particular, it has been reported that the circadian clocks are associated with tumor suppression in vivo, indicative of the

At the molecular level, the circadian clocks can be divided into three conceptual

components [10, 11]. The first is the pacemaker, dedicated to generating and sustaining circadian rhythms by receiving and integrating signals from external

Responses, and Oncogene

molecular link of the circadian clocks with cellular DDR.

theoretical foundations for cancer chronotherapy [8, 9].
