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J. Biol. Chem., Vol. 279, Issue 24, 25849-25857, June 11, 2004

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Localization of hRad9, hHus1, hRad1, and hRad17 and Caffeine-sensitive DNA Replication at the Alternative Lengthening of Telomeres-associated Promyelocytic Leukemia Body^*

Akira Nabetani, Osamu Yokoyama, and Fuyuki Ishikawa¶

From the Laboratory of Cell Cycle Regulation, Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kitashirakawa Oiwake-cho, Kyoto 606-8502 and the Laboratory of Molecular and Cellular Assembly, Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan

Telomere maintenance is essential for continued cell proliferation. Although most cells accomplish this by activating telomerase, a subset of immortalized tumors and cell lines do so in a telomerase-independent manner, a process called alternative lengthening of telomeres (ALT). DNA recombination has been shown to be involved in ALT, but the precise mechanisms remain unknown. A fraction of cells in a given ALT population contain a unique nuclear structure called APB (ALT-associated promyelocytic leukemia (PML) body), which is characterized by the presence of telomeric DNA in the PML body. Here we describe that hRad9, hHus1, and hRad1, which form a DNA clamp complex that is associated with DNA damage, as well as its clamp loader, hRad17, are constitutive components of APB. Phosphorylated histone H2AX (-H2AX), a molecular marker of double-strand breaks (DSBs), also colocalizes with some APBs. The results suggest that telomeric DNAs at APBs are recognized as DSBs. PML staining and fluorescence in situ hybridization analyses of mitotic ALT cells revealed that telomeric DNAs present at APBs are of both extrachromosomal and native telomere origins. Furthermore, we demonstrated that DNA synthesis occurs at APBs and is significantly inhibited by caffeine, an inhibitor of phosphatidylinositol 3-kinase-related kinases. Taken together, we suggest that telomeric DNAs at APBs are recognized and processed as DSBs, leading to telomeric DNA synthesis and thereby contributing to telomere maintenance in ALT cells.

Received for publication, November 19, 2003 , and in revised form, March 4, 2004.

^* This work was supported by a Center of Excellence (COE) grant, grants-in-aid for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology, and a grant-in-aid from the Virtual Research Institute of Aging of Nippon Boehringer Ingelheim. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 81-75-753-4195; Fax: 81-75-753-4197; E-mail: fishikaw{at}lif.kyoto-u.ac.jp.

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