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J. Biol. Chem., Vol. 282, Issue 20, 14882-14890, May 18, 2007

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Human TopBP1 Participates in Cyclin E/CDK2 Activation and Preinitiation Complex Assembly during G₁/S Transition^*

Yesu Jeon¹, Kyung Yong Lee², Min Ji Ko², Yong Sun Lee, Sukhyun Kang, and Deog Su Hwang³

From the Institute of Molecular Biology and Genetics, Department of Biological Sciences, Seoul National University, Seoul 151-742, Korea

Human TopBP1 with eight BRCA1 C terminus domains has been mainly reported to be involved in DNA damage response pathways. Here we show that TopBP1 is also required for G₁ to S progression in a normal cell cycle. TopBP1 deficiency inhibited cells from entering S phase by up-regulating p21 and p27, resulting in down-regulation of cyclin E/CDK2. Although co-depletion of p21 and p27 with TopBP1 restored the cyclin E/CDK2 kinase activity, however, cells remained arrested at the G₁/S boundary, showing defective chromatin-loading of replication components. Based on these results, we suggest a dual role of TopBP1 necessary for the G₁/S transition: one for activating cyclin E/CDK2 kinase and the other for loading replication components onto chromatin to initiate DNA synthesis.

Received for publication, September 26, 2006 , and in revised form, February 8, 2007.

^* This work was supported by grants from the National R&D Program for Cancer Control, Ministry of Health and Welfare (0420240-2) and Basic Research Promotion Fund of Korea Research Foundation (KRF-2005-070-C00089), Republic of Korea (to D. S. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by Research Intern Program Fellowship from the Ministry of Education, Republic of Korea.

² Supported by the second stage of the BK21 Project.

³ To whom correspondence should be addressed. Tel.: 82-2-880-7524; Fax: 82-2-873-7524; E-mail: dshwang{at}snu.ac.kr.

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