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J. Biol. Chem., Vol. 282, Issue 13, 9346-9357, March 30, 2007
Geminin Cleavage during Apoptosis by Caspase-3 Alters Its Binding Ability to the SWI/SNF Subunit Brahma*![]() ![]() ![]() 1
From the
Geminin has been proposed to coordinate cell cycle and differentiation events through balanced interactions with the cell cycle regulator Cdt1 and with homeobox transcription factors and chromatin remodeling activities implicated in cell fate decisions. Here we show that Geminin is cleaved in primary cells and cancer cell lines induced to undergo apoptosis by a variety of stimuli. Geminin targeting is mediated by caspase-3 both in vivo and in vitro. Two sites at the carboxyl terminus of Geminin (named C1 and C2) are cleaved by the caspase, producing truncated forms of Geminin. We provide evidence that Geminin cleavage is regulated by phosphorylation. Casein kinase II alters Geminin cleavage at site C1 in vitro, whereas mutating phosphorylation competent Ser/Thr residues proximal to site C1 affects Geminin cleavage in vivo. We show that truncated Geminin produced by cleavage at C1 can promote apoptosis. In contrast, Geminin cleaved at site C2 has lost the ability to interact with Brahma (Brm), a catalytic subunit of the SWI/SNF chromatin remodeling complex, while binding efficiently to Cdt1, indicating that targeting of Geminin during apoptosis differentially affects interactions with its binding partners.
Received for publication, December 19, 2006 , and in revised form, January 29, 2007. * This work was supported by the Association for International Cancer Research and the Human Frontiers Science Program Organization. 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. 1 To whom correspondence should be addressed: Laboratory of General Biology, School of Medicine, University of Patras, 26500 Rio, Patras, Greece. Tel.: 30-2610-997621; Fax: 30-2610-991769; E-mail: lygerou{at}med.upatras.gr.
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