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Molecular and Cellular Biology, July 2005, p. 5355-5362, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5355-5362.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The DNA Damage-Inducible UbL-UbA Protein Ddi1 Participates in Mec1-Mediated Degradation of Ho Endonuclease

Ludmila Kaplun, Regina Tzirkin, Anya Bakhrat, Nitzan Shabek, Yelena Ivantsiv, and Dina Raveh^*

Department of Life Sciences, Ben Gurion University of the Negev, Beersheba 84105, Israel

Received 9 January 2005/ Returned for modification 10 February 2005/ Accepted 23 March 2005

Ho endonuclease initiates a mating type switch by making a double-strand break at the mating type locus, MAT. Ho is marked by phosphorylation for rapid destruction by functions of the DNA damage response, MEC1, RAD9, and CHK1. Phosphorylated Ho is recruited for ubiquitylation via the SCF ubiquitin ligase complex by the F-box protein, Ufo1. Here we identify a further DNA damage-inducible protein, the UbL-UbA protein Ddi1, specifically required for Ho degradation. Ho interacts only with Ddi1; it does not interact with the other UbL-UbA proteins, Rad23 or Dsk2. Ho must be ubiquitylated to interact with Ddi1, and there is no interaction when Ho is produced in mec1 or ufo1 mutants that do not support its degradation. Ddi1 binds the proteasome via its N-terminal ubiquitinlike domain (UbL) and interacts with ubiquitylated Ho via its ubiquitin-associated domain (UbA); both domains of Ddi1 are required for association of ubiquitylated Ho with the proteasome. Despite being a nuclear protein, Ho is exported to the cytoplasm for degradation. In the absence of Ddi1, ubiquitylated Ho is stabilized and accumulates in the cytoplasm. These results establish a role for Ddi1 in the degradation of a natural ubiquitylated substrate. The specific interaction between Ho and Ddi1 identifies an additional function associated with DNA damage involved in its degradation.

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* Corresponding author. Mailing address: Ben Gurion University of the Negev, Life Sciences, P.O. Box 653, Beersheba 84105, Israel. Phone: 972-8-646-1371. Fax: 972-8-647-9190. E-mail: raveh{at}bgumail.bgu.ac.il.

Both authors contributed equally.

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Molecular and Cellular Biology, July 2005, p. 5355-5362, Vol. 25, No. 13
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.13.5355-5362.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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