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Molecular and Cellular Biology, June 2005, p. 5171-5182, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.5171-5182.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mutation of SENP1/SuPr-2 Reveals an Essential Role for Desumoylation in Mouse Development

Taihei Yamaguchi,1,{dagger} Prashant Sharma,1,§ Meropi Athanasiou,2,§ Amit Kumar,1 Satoru Yamada,1,§ and Michael R. Kuehn1*

Laboratory of Protein Dynamics and Signaling Basic Research Program, SAIC—Frederick, National Cancer Institute, NCI—Frederick, Frederick, Maryland 217022

Received 30 March 2004/ Returned for modification 10 May 2004/ Accepted 11 March 2005

The covalent modification of proteins by the small ubiquitin-like protein SUMO has been implicated in the regulation of numerous biological processes, including nucleocytoplasmic transport, genomic stability, and gene transcription. Sumoylation occurs by a multienzyme process similar to ubiquitination and, in Saccharomyces cerevisiae, is reversed by desumoylating enzymes encoded by the Ulp1 and Smt4/Ulp2 genes. The physiological importance of desumoylation has been revealed by mutations in either gene, which lead to nonoverlapping defects in cell cycle transition and meiosis. Several mammalian Ulp homologues have been identified, but, to date, nothing is known of the phenotypic effects of their loss of function. Here, we describe a random retroviral insertional mutation of one homolog, mouse SENP1/SuPr-2. The mutation causes increased steady-state levels of the sumoylated forms of a number of proteins and results in placental abnormalities incompatible with embryonic development. Our findings provide the first insight into the critical importance of regulating sumoylation in mammals.

* Corresponding author. Mailing address: Laboratory of Protein Dynamics and Signaling, NCI-Frederick, Bldg. 560, Rm. 12-90, Frederick, MD 21702. Phone: (301) 846-7451. Fax: (301) 846-1666. E-mail: mkuehn{at}mail.nih.gov.

{dagger} Present address: Kagoshima University Dental School, Department of Preventive Dentistry, Sakuragaoka 8-35-1, Kagoshima-shi, Kagoshima 890-8544, Japan.

{ddagger} Present address: Osaka University Graduate School of Dentistry, Department of Periodontology, Division of Oral Biology and Disease Control, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan.

§ P.S. and M.A. contributed equally to this work.

Molecular and Cellular Biology, June 2005, p. 5171-5182, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.5171-5182.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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