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Originally published In Press as doi:10.1074/jbc.M005319200 on September 5, 2000

J. Biol. Chem., Vol. 275, Issue 47, 36892-36898, November 24, 2000
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Identification of a Functional Domain in a GADD45-mediated G2/M Checkpoint*

Qin YangDagger , Anne ManiconeDagger §, Jill D. Coursen, Steven P. Linke, Makoto Nagashima, Marshonna Forgues, and Xin Wei Wang||

From the Laboratory of Human Carcinogenesis, DBS, NCI, National Institutes of Health, Bethesda, Maryland 20892

Cell cycle checkpoints are essential for the maintenance of genomic stability in response to DNA damage. We demonstrated recently that GADD45, a DNA damage-inducible protein, activates a G2/M checkpoint induced by either UV radiation or alkylating agents. GADD45 can interact in vivo with the G2 cell cycle-specific kinase, Cdc2, proliferating cell nuclear antigen (PCNA), and the cell cycle kinase inhibitor p21waf1. The ability of GADD45 to induce a G2/M arrest may be caused in part by the inhibition of Cdc2 kinase activity. Here, we report the identification of a region of GADD45 that is involved in this G2/M checkpoint. Mutants of GADD45 that lacked either the first 35 or the last 80 residues still retained an ability to induce G2/M arrest. A mutant with a deletion of the central region (residues 50-76), which is conserved in the family members GADD45beta and GADD45gamma , lacked such activity. This mutant also lacked an ability to bind to Cdc2, PCNA, and p21waf1 in vivo. Consistently, either GADD45beta or GADD45gamma bind to Cdc2 in vivo. However, unlike GADD45, neither GADD45beta nor GADD45gamma inhibited the Cdc2 kinase or induced G2/M arrest. The unique effect of GADD45 may be caused by the presence of a region containing DEDDDR residues. Alanine substitutions in the region abolished GADD45 induction of a G2/M arrest and its inactivation of the Cdc2 kinase but not its binding to Cdc2, PCNA, or p21waf1. Therefore, the binding of GADD45 to Cdc2 was insufficient to induce a G2/M arrest, and additional activity contributed by the DEDDDR residues may be necessary to regulate the G2/M checkpoint.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger These authors contributed equally to this work.

§ A Howard Hughes Medical Institute-National Institutes of Health Research Scholar.

Present address: Genzyme Corp., One Kendall Square, Cambridge, MA 02139-1562.

|| To whom correspondence should be addressed: LHC, NCI, National Institutes of Health, 37 Convent Dr., MSC 4255, Bldg. 37, Rm. 2C08, Bethesda, MD 20892-4255; Tel.: 301-496-2099; Fax: 301-496-0497; Email: xin_wei_wang@nih.gov.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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