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J. Biol. Chem., Vol. 280, Issue 25, 23566-23575, June 24, 2005

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Defects in SUMO (Small Ubiquitin-related Modifier) Conjugation and Deconjugation Alter Cell Sensitivity to DNA Topoisomerase I-induced DNA Damage^*

Hervé R. Jacquiau, Robert C. A. M. van Waardenburg, Robert J. D. Reid¶, Michael H. Woo||, Hong Guo, Erica S. Johnson**, and Mary-Ann Bjornsti

From the Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 and ^**Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Eukaryotic DNA topoisomerase I (Top1p) has important functions in DNA replication, transcription, and recombination. This enzyme also constitutes the cellular target of camptothecin (CPT), which induces S-phase-dependent cytotoxicity. To define cellular pathways that regulate cell sensitivity to Top1p-induced DNA lesions, we described a yeast genetic screen for conditional tah (top1T722A-hypersensitive) mutants with enhanced sensitivity to low levels of the CPT mimetic mutant top1T722A (Reid, R. J., Fiorani, P., Sugawara, M., and Bjornsti, M. A. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 11440–11445; Fiorani, P., Reid, R. J., Schepis, A., Jacquiau, H. R., Guo, H., Thimmaiah, P., Benedetti, P., and Bjornsti, M. A. (2004) J. Biol. Chem. 279, 21271–21281). Here we report that tah mutant ubc9–10 harbors a hypomorphic allele of UBC9, which encodes the essential SUMO (small ubiquitin-related modifier) E2-conjugating enzyme. The same conditional ubc9P123L mutant was also isolated in an independent screen for enhanced sensitivity to a distinct Top1p poison, Top1N726Hp. The ubc9–10 mutant exhibited a decrease in global protein sumoylation and increased sensitivity to a wide range of DNA-damaging agents independent of Top1p. Deletion of the Ulp2 SUMO protease failed to restore ubc9–10 cell resistance to Top1p poisons or hydroxyurea yet adversely affected wild-type TOP1 cell genetic stability and sensitivity to hydroxyurea. Moreover, although mutation of different consensus SUMO sites in the N terminus and linker region of yeast Top1p failed to recapitulate ubc9–10 mutant phenotypes, they revealed distinct and subtle effects on cell sensitivity to CPT. These results provide insights into the complexities of SUMO conjugation and the confounding effects of SUMO modification on Top1p function and cell sensitivity to genotoxic agents.

Received for publication, January 26, 2005 , and in revised form, April 6, 2005.

^* This work was supported in part by National Institutes of Health Grants CA58755 and CA23099 (to M.-A. B.), National Institutes of Health Grant GM62268 (to E. S. J.), NCI Cancer Center Core Grant CA21765, and the American Lebanese Syrian Associate Charities. 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.

Both authors contributed equally to this work.

^¶ Present address: Department of Genetics and Development, Columbia University, College of Physicians and Surgeons, New York, NY 10032.

^|| Present address: Clinical Discovery, Bristol-Myers Squibb, Lawrenceville, NJ 08543.

To whom correspondence should be addressed: Dept. of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Tel.: 901-495-2315; E-mail: Mary-Ann.Bjornsti{at}stjude.org.

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