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J. Biol. Chem., Vol. 281, Issue 18, 12218-12226, May 5, 2006

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Nuclear Import of Ho Endonuclease Utilizes Two Nuclear Localization Signals and Four Importins of the Ribosomal Import System^*

Anya Bakhrat¹², Keren Baranes¹, Oleg Krichevsky³, Inna Rom, Gabriel Schlenstedt^¶4, Shmuel Pietrokovski^||5, and Dina Raveh⁶

From the Departments of Life Sciences and Physics, Ben Gurion University of the Negev, P. O. Box 653, 84105 Beersheba, Israel, the ^¶Department of Medical Biochemistry and Molecular Biology, Saarlandes University, 66421 Homburg, Germany, and the ^||Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel

Activity of Ho, the yeast mating switch endonuclease, is restricted to a narrow time window of the cell cycle. Ho is unstable and despite being a nuclear protein is exported to the cytoplasm for proteasomal degradation. We report here the molecular basis for the highly efficient nuclear import of Ho and the relation between its short half-life and passage through the nucleus. The Ho nuclear import machinery is functionally redundant, being based on two bipartite nuclear localization signals, recognized by four importins of the ribosomal import system. Ho degradation is regulated by the DNA damage response and Ho retained in the cytoplasm is stabilized, implying that Ho acquires its crucial degradation signals in the nucleus. Ho arose by domestication of a fungal VMA1 intein. A comparison of the primary sequences of Ho and fungal VMA1 inteins shows that the Ho nuclear localization signals are highly conserved in all Ho proteins, but are absent from VMA1 inteins. Thus adoption of a highly efficient import strategy occurred very early in the evolution of Ho. This may have been a crucial factor in establishment of homothallism in yeast, and a key event in the rise of the Saccharomyces sensu stricto.

Received for publication, January 10, 2006 , and in revised form, February 22, 2006.

^* This work was supported in part by the Association for International Cancer Research (AICR), the German-Israel Foundation for Scientific Research and Development, the Israel Cancer Research Fund, by a donation by Helene Miller through the Perpetual fund in memory of Daniel Miller to the Israel Cancer Association, and by European Union Contract HPRN-CT-2002-00238 (to D. R.). 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 Both authors contributed equally to the results of this article.

² Kreitmann Fellow of the Ben Gurion University Graduate School.

³ Supported by the Israel Science Fund.

⁴ Supported by the Deutsche Forschungsgemeinschaft.

⁵ Supported by the Israel Science Fund and the Leo and Julia Forchheimer Center for Molecular Genetics. To whom correspondence may be addressed. Tel.: 972-8-934-2747; Fax: 972-8-934-4108; E-mail: shmuel.pietrokovski{at}weizmann.ac.il. ⁶ To whom correspondence may be addressed. Tel.: 972-8-646-1371; Fax: 972-8-647-9190; E-mail: raveh{at}bgumail.bgu.ac.il.

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