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

Abstract

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.

ACKNOWLEDGMENTS

We thank Allison Galica for technical support, Lionel Feigenbaum and the NCI Transgenic Core for generation of transgenic mice, Philippe Soriano for ROSA26 constructs, Yongsok Kim for the original GFP-SUMO-1 construct, Mary Dasso for helpful discussions and anti-SUMO-1 and anti-SUMO-2 antisera, and Allan M. Weissman and Stan Lipkowitz for critical comments on the manuscript. Analysis of real-time PCR results utilized software developed by the Gene Expression Laboratory, SAIC, NCI—Frederick.

Animal care was provided in accordance with the procedures outlined in the “Guide for the care and use of laboratory animals” (NIH publication no. 86-23, 1985).

This study has been funded in part by federal funds from the National Cancer Institute under contract no. NO1-CO-12400.

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