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Molecular and Cellular Biology, May 2003, p. 3497-3505, Vol. 23, No. 10
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.10.3497-3505.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Two Ubiquitin-Conjugating Enzymes, UbcP1/Ubc4 and UbcP4/Ubc11, Have Distinct Functions for Ubiquitination of Mitotic Cyclin

Hiroaki Seino,^1* Tsutomu Kishi,^1,2 Hideo Nishitani,³ and Fumiaki Yamao¹

Division of Mutagenesis, National Institute of Genetics, Mishima, Shizuoka 411-8540,¹ Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582,³ PRESTO, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan²

Received 23 October 2002/ Returned for modification 4 December 2002/ Accepted 27 February 2003

Cell cycle events are regulated by sequential activation and inactivation of Cdk kinases. Mitotic exit is accomplished by the inactivation of mitotic Cdk kinase, which is mainly achieved by degradation of cyclins. The ubiquitin-proteasome system is involved in this process, requiring APC/C (anaphase-promoting complex/cyclosome) as a ubiquitin ligase. In Xenopus and clam oocytes, the ubiquitin-conjugating enzymes that function with APC/C have been identified as two proteins, UBC4 and UBCx/E2-C. Previously we reported that the fission yeast ubiquitin-conjugating enzyme UbcP4/Ubc11, a homologue of UBCx/E2-C, is required for mitotic transition. Here we show that the other fission yeast ubiquitin-conjugating enzyme, UbcP1/Ubc4, which is homologous to UBC4, is also required for mitotic transition in the same manner as UbcP4/Ubc11. Both ubiquitin-conjugating enzymes are essential for cell division and directly required for the degradation of mitotic cyclin Cdc13. They function nonredundantly in the ubiquitination of CDC13 because a defect in ubcP1/ubc4⁺ cannot be suppressed by high expression of UbcP4/Ubc11 and a defect in ubcP4/ubc11⁺ cannot be suppressed by high expression of UbcP1/Ubc4. In vivo analysis of the ubiquitinated state of Cdc13 shows that the ubiquitin chains on Cdc13 were short in ubcP1/ubc4 mutant cells while ubiquitinated Cdc13 was totally reduced in ubcP4/ubc11 mutant cells. Taken together, these results indicate that the two ubiquitin-conjugating enzymes play distinct and essential roles in the degradation of mitotic cyclin Cdc13, with the UbcP4/Ubc11-pathway initiating ubiquitination of Cdc13 and the UbcP1/Ubc4-pathway elongating the short ubiquitin chains on Cdc13.

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* Corresponding author. Mailing address: Division of Mutagenesis, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan. Phone: 81-55-981-6750. Fax: 81-55-981-6751. E-mail: hseino{at}lab.nig.ac.jp.

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Molecular and Cellular Biology, May 2003, p. 3497-3505, Vol. 23, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.10.3497-3505.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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