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Vol. 16, Issue 12, 5551-5562, December 2005

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Dimerization of the ATRIP Protein through the Coiled-Coil Motif and Its Implication to the Maintenance of Stalled Replication Forks

Department of Geriatric Medicine, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Morioka-cho, Obu, Aichi 474-8522, Japan

Submitted May 16, 2005; Revised September 12, 2005; Accepted September 13, 2005
Monitoring Editor: Mark Solomon

ATR (ATM and Rad3-related), a PI kinase-related kinase (PIKK), has been implicated in the DNA structure checkpoint in mammalian cells. ATR associates with its partner protein ATRIP to form a functional complex in the nucleus. In this study, we investigated the role of the ATRIP coiled-coil domain in ATR-mediated processes. The coiled-coil domain of human ATRIP contributes to self-dimerization in vivo, which is important for the stable translocation of the ATR-ATRIP complex to nuclear foci that are formed after exposure to genotoxic stress. The expression of dimerization-defective ATRIP diminishes the maintenance of replication forks during treatment with replication inhibitors. By contrast, it does not compromise the G2/M checkpoint after IR-induced DNA damage. These results show that there are two critical functions of ATR-ATRIP after the exposure to genotoxic stress: maintenance of the integrity of replication machinery and execution of cell cycle arrest, which are separable and are achieved via distinct mechanisms. The former function may involve the concentrated localization of ATR to damaged sites for which the ATRIP coiled-coil motif is critical.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

^* Present address: Department of Regulation Biology, Faculty of Science, Saitama University, Sakura-ku, Saitama 338-8570, Japan.

Address correspondence to: Akira Matsuura (amatsuur{at}nils.go.jp).

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