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Emerging Connection Between Centrosome and DNA Repair Machinery

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Emerging Connection Between Centrosome and DNA Repair Machinery J. Radiat. Res., 50, 295–301 (2009) Review Emerging Connection Between Centrosome and DNA Repair Machinery Mikio SHIMADA* and Kenshi KOMATSU Centrosome/Tumorigenesis/Genome instability/DNA repair. Centrosomes function in proper cell division in animal cells. The centrosome consists of a pair of centrioles and the surrounding pericentriolar matrix (PCM). After cytokinesis, daughter cells each acquire one centrosome, which subsequently duplicates at the G1/S phase in a manner that is dependent upon CDK2/cyclin-E activity. Defects in the regulation of centrosome duplication lead to tumorigenesis through abnormal cell division and resulting inappropriate chromosome segregation. Therefore, maintenance of accurate centrosome number is important for cell fate. Excess number of centrosomes can be induced by several factors including ionizing radiation (IR). Recent studies have shown that several DNA repair pro- teins localize to the centrosome and are involved in the regulation of centrosome number possibly through cell cycle checkpoints or direct modification of centrosome proteins. Furthermore, it has been reported that the development of microcephaly is likely caused by defective expression of centrosome proteins, such as ASPM, which are also involved in the response to IR. The present review highlights centrosome dupli- cation in association with genotoxic stresses and the regulatory mechanism mediated by DNA repair proteins. known to cause tumorigenesis due to defective maintenance INTRODUCTION of centrosomes, in addition to impaired DNA repair. In light of centrosome maintenance with DNA repair pro- The centrosome, first described by Theodor Boveri in the early 1900’s, is an important organelle necessary for proper cell division in mammalian cells. The centrosome has a role as a microtubule organizing center (Fig. 1). Although it must duplicate once per cell cycle division, an excess number of centrosomes can be induced by both genotoxic agents, including ionizing radiation (IR), and aberrant cell cycle checkpoints.1,2) This abnormal centrosome number results in the formation of multipolar spindles and aneuploidy. Since aneuploidy is frequently observed in cancer cells,3,4) the excess number of centrosomes might facilitate tumori- genesis through aneuploid cells.5–7) Thus, regulation of centrosome duplication is indispensable for proper cell pro- liferation. Recent studies have demonstrated centrosomal localization and involvement in its maintenance of several DNA damage response and repair proteins, including NBS1, BRCA1 and ATM/ATR kinases. The dysfunction of these proteins is Fig. 1. Structure of the centrosome. The centrosome consists of a pair of centrioles and the surrounding pericentriolar matrix *Corresponding author: Phone: +81-75-753-7567, Fax: +81-75-753-7564, (PCM). The mother centriole has a set of appendages at the distal E-mail: [email protected] ends, whereas the daughter centriole does not. Centrosomes func- Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto tion as a microtubule organizing center (MTOC) at mitosis, in University, Konoecho, Sakyo-ku, Kyoto 606-8501, Japan. which γ-tubulin provides a microtubule anchoring machinery by doi:10.1269/jrr.09039 forming a γ-tubulin ring complex (γ-TuRC). J. Radiat. Res., Vol. 50, No. 4 (2009); http://jrr.jstage.jst.go.jp 296 M. Shimada and K. Komatsu teins, we discuss the mechanisms of centrosome mainte- nance after genotoxic stresses, including IR, and how these failures contribute to tumorigenesis. CENTROSOMES AND GENOME INSTABILITY Bipolar spindle formation with two centrosomes is required for normal cytokinesis.8) Supernumerary centro- somes, defined by more than two centrosomes, might cause multiple spindle pole formation and lead to abnormal cell division or apoptosis.9) For example, most tripolar spindle cells can undergo cytokinesis; however, they generate aneu- ploid cells. Cells containing more than three polar spindles Fig. 2. Centrosome duplication cycle. Centrosomes duplicate fail to undergo cytokines and cause cell cycle arrest,3,10) from late-G1 phase to early-S phase. Activity of CDK2/cyclin-E, which is mediated by p53 signaling and leads to apoptosis. Aurora A, PLK2, and PLK4 are indispensable for centrosome On the other hand, p53 mutated cells continue cell cycle pro- duplication. After duplication, centrosomes mature throughout G2 gression, which might lead to tumorigenesis. Furthermore, and then divide during mitosis. some cells containing overduplicated centrosomes can form pseudo-bipolar spindles, in which the excess centrosomes are positioned to a bipolar axis in a process called centro- has also been implicated in the regulation of centrosome some clustering. Therefore, the presence of overduplicated duplication. centrosomes does not necessarily result in the formation of CDK2/cyclin-E has several target proteins in centrosome multipolar spindles. Cells with pseudo-bipolar spindles can regulation. Nucleophosmin (NPM) functions as molecular progress through cytokinesis, but are prone to chromosome chaperone in several cellular events and is frequently segregation errors. As a result, overduplicated centrosomes mutated in cancer cells.18) NPM localizes at centrioles to frequently generate polyploid cells through abnormal segre- function in the pairing of two centrioles. NPM is phospho- gation.11,12) Genome-wide RNAi screening by Kwon et al rylated by CDK2/cyclin-E and then dissociates from the revealed the suppressing mechanism of multipolar mitosis centrosome; this is an initial event in centrosome duplica- by spindle assembly checkpoint (SAC), which contains tion. Mad2, Bub1, and CENP-E.13) SAC machinery contributes to There are several centrosome regulation kinases, such as the prevention of tumorigenesis arising from centrosome polo-like kinase 2 (PLK2), polo-like kinase 4 (PLK4), and overduplication. Aurora A. These kinases are frequently overexpressed in Exposure to IR induces overduplication of centrosomes, cancer cells. PLK2 and PLK4 localize at centrosomes, and which, in turn, causes abnormal cytokinesis. In many cases, the siRNA knockdown of PLK2 or PLK4 suppresses the ini- failure to proper cell division results in mitotic cell death. tiation of centrosome duplication.19,20) Aurora A also local- Therefore, IR-induced centrosome overduplication may izes at centrosomes, and overexpression of this kinase leads cause mitotic cell death. to centrosome overduplication.21,22) CENTROSOME DUPLICATION CYCLE DNA REPAIR PROTEINS AND CENTROSOMES Like DNA synthesis, centrosome duplication is synchro- DNA double strand breaks are repaired by two major nized with the cell cycle and initiated at S phase (Fig. 2). pathways, which are homologous recombination (HR), and However, when p53-mutated cells arrest at the S phase upon non-homologous end-joining (NHEJ) repair. ATM/ATR treatment with hydroxyurea, centrosome duplication contin- kinases, NBS1-MRE11-RAD50 complex, BRCA1 and ues despite the block of DNA synthesis. Whereas CDK2/ BRCA2 are involved in HR repair. DNA-PKcs, Ku70 and cyclin-E is known as an important factor for DNA synthesis, Ku80 are involved in NHEJ repair. its activity also has a crucial role in the initiation of cen- Recently, there have been many reports showing that trosome duplication.14–16) The progression of centrosome DNA repair proteins localize at the centrosome. In addition, duplication after inhibition of DNA synthesis is likely due HR repair proteins are suggested to be involved in cen- to high CDK2 activity in the S phase, since centrosomes are trosome regulation. not duplicated in the absence of CDK2/cyclin-E activa- Ataxia-telangiectasia (AT), which is caused by a mutation tion.17) Cyclin-E has a centrosome localization signal (CLS), in ATM, is an autosomal recessive disorder characterized by and the CLS deletion mutant of cyclin-E cannot localize at cerebellar ataxia, telangiectasia, immunodeficiency, and centrosomes. CDK2 forms a complex with cyclin-A, which predisposition to malignancy.23) AT patient cells show hyper- J. Radiat. Res., Vol. 50, No. 4 (2009); http://jrr.jstage.jst.go.jp DNA Repair Proteins and Centrosomes 297 sensitivity to IR, defective cell cycle checkpoints, and chro- nucleus and at centrosomes. After exposure to IR, PARP-1 mosomal instability. ATM is a serine/threonine kinase, is recruited to damage sites and regulates several DNA repair which is a member of the phosphatidylinositol 3-kinase proteins by polyADP-ribosylations.49) Cells from PARP1- (PI3-K)-like family. ATM auto-phosphorylates itself for its deficient mice show centrosome overduplication.50) However, own activation at an initial step of the DNA damage res- there are so far no reports of any human syndrome asso- ponse. ATM localizes at centrosomes and regulates the ciated with PARP mutations. number of centrosomes through the cell cycle check- Centrosomes also contain other HR repair proteins includ- point.24,25) The knockdown of ATM by siRNA suppresses ing SMC1 (Fig. 3).51–53) Expression of dominant-negative centrosome duplication, while exposure to IR induces an RAD51 results in centrosome overduplication. Furthermore, excess number of centrosomes. conditional deletion of RAD51 leads to centrosome overdu- ATR (ATM- and Rad3-related) is one of proteins respon- plication in an ATM-dependent manner at the prolonged G2 sible for Seckel syndrome, an autosomal recessive disorder phase.54) Similarly, inactivation of RAD51B, RAD51C, characterized by intrauterine growth retardation, severe pro- RAD51D, XRCC2,
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