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Conjugation of small ubiquitin-like modifiers (SUMOs) to substrate proteins is a posttranslational protein modification that affects a diverse range of physiological processes. Global inhibition of SUMO conjugation in mice results in embryonic lethality, reflecting the importance of the SUMO pathways for embryonic development. Here, we demonstrated that SUMO1 overexpression was not well tolerated in murine embryonic carcinoma and embryonic stem (ES) cells and that only a few clones were recovered after transduction with vectors delivering SUMO1 expression constructs. Differentiated NIH/3T3 cells overexpress SUMO1 without deleterious effects and maintain high levels of both conjugated and free forms of SUMO1. The few embryonic cells surviving after forced overexpression retained all their SUMO1 in the form of a few high-molecular-weight conjugates and maintained undetectable levels of free SUMO1. The absence of free SUMO in embryonic cells was seen specifically upon overexpression of SUMO1, but not SUMO2. Moreover, blocking SUMO1 conjugation to endogenous substrates by C-terminal mutations of SUMO1 or by overexpression of a SUMO1 substrate "sponge" or by overexpression of the deSUMOylating enzyme SUMO-specific peptidase 1 (SENP1) dramatically restored free SUMO1 overexpression. The data suggest that overexpression of SUMO1 protein leading to an excess accumulation of critical SUMO1-conjugated substrates is not tolerated in embryonic cells. Surviving embryonic cells exhibit SUMO1 conjugation to allowed substrates but a complete absence of free SUMO1. IMPORTANCE Embryonic stem (ES) cells exhibit unusual transcriptional, proteomic, and signal response profiles, reflecting their unusual needs for rapid differentiation and replication. The work reported here demonstrated that mouse embryonic cell lines did not tolerate the overexpression of SUMO1, the small ubiquitin-like modifier protein that is covalently attached to many substrates to alter their intracellular localization and functionality. Forced SUMO1 overexpression is toxic to ES cells, and surviving cell populations adapt by dramatically reducing the levels of free SUMO1. Such a response is not seen in differentiated cells or with SUMO2 or with nonconjugatable SUMO1 mutants or in the presence of a SUMO1 "sponge" substrate that accepts the modification. The findings suggest that excess SUMO1 modification of specific substrates is not tolerated by embryonic cells and highlight a distinctive need for these cells to control the levels of SUMO1 available for conjugation.

Embryonic Cells Redistribute SUMO1 upon Forced SUMO1 Overexpression