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Molecular and Cellular Biology, July 2006, p. 4958-4969, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.00160-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Distinct Functional Domains of Ubc9 Dictate Cell Survival and Resistance to Genotoxic Stress

Robert C. A. M. van Waardenburg,1 David M. Duda,2 Cynthia S. Lancaster,1 Brenda A. Schulman,2,3 and Mary-Ann Bjornsti1*

Department of Molecular Pharmacology,1 Department of Structural Biology and Genetics/Tumor Cell Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105,2 Howard Hughes Medical Institute3

Received 27 January 2006/ Accepted 29 March 2006

Covalent modification with SUMO alters protein function, intracellular localization, or protein-protein interactions. Target recognition is determined, in part, by the SUMO E2 enzyme, Ubc9, while Siz/Pias E3 ligases may facilitate select interactions by acting as substrate adaptors. A yeast conditional Ubc9P123L mutant was viable at 36°C yet exhibited enhanced sensitivity to DNA damage. To define functional domains in Ubc9 that dictate cellular responses to genotoxic stress versus those necessary for cell viability, a 1.75-Å structure of yeast Ubc9 that demonstrated considerable conservation of backbone architecture with human Ubc9 was solved. Nevertheless, differences in side chain geometry/charge guided the design of human/yeast chimeras, where swapping domains implicated in (i) binding residues within substrates that flank canonical SUMOylation sites, (ii) interactions with the RanBP2 E3 ligase, and (iii) binding of the heterodimeric E1 and SUMO had distinct effects on cell growth and resistance to DNA-damaging agents. Our findings establish a functional interaction between N-terminal and substrate-binding domains of Ubc9 and distinguish the activities of E3 ligases Siz1 and Siz2 in regulating cellular responses to genotoxic stress.

* Corresponding author. Mailing address: Dept. of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-2315. Fax: (901) 495-4293. E-mail: mary-ann.bjornsti{at}stjude.org.

Molecular and Cellular Biology, July 2006, p. 4958-4969, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.00160-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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