**3. Centrosomes and the cell cycle**

Centrosome duplication is controlled by several cell-cycle regulators (Fukasawa, 2007). The cyclin E/CDK2 complex is responsible for initiating DNA synthesis and regulates cell-cycle progression (Matsumoto et al., 1999). This complex also contributes to centrosome duplication (Fig. 3). Cyclin E contains the centrosome localization signal (CLS), and overexpression of mutated cyclin E through a CLS deletion results in failed centrosome duplication (Matsumoto and Maller, 2002). The *CDKN1A* product, p21, is a negative regulator of CDK2. As the expression of p21 is regulated by p53-dependent transcription, the absence of p53 abrogates p21-dependent repression of CDK2 and subsequently leads to centrosome duplication. The DNA synthesis inhibitor, hydroxyurea (HU), induces cell-cycle arrest at the G1/S phase. Cells possessing wild-type p53 prevent HU-induced overduplication of centrosomes by inhibiting CDK2 through p53/p21. In contrast, the absence of functional p53 abolishes the p21-dependent repression of CDK2, leading to centrosome amplification. p53

Centrosomes are located at the periphery of the nucleus and consist of a mother centriole and a daughter centriole, surrounded by the pericentriolar material (PCM). The γ-tubulin ring complex

Centrosome duplication is controlled by several cell-cycle regulators (Fukasawa, 2007). The cyclin E/CDK2 complex is responsible for initiating DNA synthesis and regulates cell-cycle progression (Matsumoto et al., 1999). This complex also contributes to centrosome duplication (Fig. 3). Cyclin E contains the centrosome localization signal (CLS), and overexpression of mutated cyclin E through a CLS deletion results in failed centrosome duplication (Matsumoto and Maller, 2002). The *CDKN1A* product, p21, is a negative regulator of CDK2. As the expression of p21 is regulated by p53-dependent transcription, the absence of p53 abrogates p21-dependent repression of CDK2 and subsequently leads to centrosome duplication. The DNA synthesis inhibitor, hydroxyurea (HU), induces cell-cycle arrest at the G1/S phase. Cells possessing wild-type p53 prevent HU-induced overduplication of centrosomes by inhibiting CDK2 through p53/p21. In contrast, the absence of functional p53 abolishes the p21-dependent repression of CDK2, leading to centrosome amplification. p53

(γ-TuRC) binds to the PCM to form microtubules.

**3. Centrosomes and the cell cycle** 

Fig. 1. Centrosome structure.

(A) Two centrosomes separate at the two poles, and normal cell division progresses. (B) Overduplicated centrosomes accumulate into the two poles and form a pseudo-bipolar spindle, leading to improper cell division and chromosome instability. (C) Overduplicated centrosomes form a multipolar spindle, leading to a failure of cytokinesis and mitotic catastrophe.

Fig. 2. Cell division during mitosis with normal and abnormal number of centrosomes.

also contributes to abrogation of the linkage between the cell cycle and the centrosome duplication cycle because the p53-dependent G2/M checkpoint is activated in an ataxia telangiectasia mutated (ATM)/ATM- and Rad3-related (ATR)-dependent manner after DNA damage such as from irradiation.
