The small ubiquitin-related modifier SUMO posttranslationally modifies many proteins with roles in diverse processes including regulation of transcription, chromatin structure, and DNA repair. Similar to nonproteolytic roles of ubiquitin, SUMO modification regulates protein localization and activity. Some proteins can be modified by SUMO and ubiquitin, but with distinct functional consequences. It is possible that the effects of ubiquitination and SUMOylation are both largely due to binding of proteins bearing specific interaction domains. Both modifications are reversible, and in some cases dynamic cycles of modification may be required for activity. Studies of SUMO and ubiquitin in the nucleus are yielding new insights into regulation of gene expression, genome maintenance, and signal transduction.Reversible posttranslational modifications are widely used to dynamically regulate protein activity. Proteins can be modified by small chemical groups, sugars, lipids, and even by covalent attachment of other polypeptides. The most well-known example of a polypeptide modifier is ubiquitin. Posttranslational modification by ubiquitin plays a central role in targeting proteins for proteolytic degradation by the proteasome, although covalent attachment of ubiquitin to proteins can also regulate localization and/or activity independent of proteolysis. In addition to ubiquitin, there are several ubiquitin-like proteins (UbLs) that can also be conjugated to, and alter the function of, substrate proteins. One Ubl in particular, the small ubiquitin-related modifier (SUMO) has been shown to covalently modify a large number of proteins with important roles in many cellular processes including gene expression, chromatin structure, signal transduction, and maintenance of the genome. The enzymatic machinery that adds and removes SUMO is similar to, but distinct from, the ubiquitination machinery. Posttranslational modification by SUMO has not been generally associated with increased protein degradation. Rather, similar to nonproteolytic roles of ubiquitin, SUMO modification regulates protein localization and activity.This review focuses on recent advances in our understanding of SUMO function and regulation, drawing on a limited set of examples relating to gene expression, chromatin structure, and DNA repair. Comparison of SUMO and ubiquitin activities in the nucleus reveals interesting differences in function and suggests surprising similarities in mechanism. Thus, for example, modification of transcription factors and histones by ubiquitin is generally associated with increased gene expression whereas modification of transcription factors and histones by SUMO is generally associated with decreased gene expression. In some cases, SUMO and ubiquitin may directly compete for modification of target lysines. Despite the different functional consequences associated with these modifications, current data supports the hypothesis that SUMO, like ubiquitin, largely functions to promote interactions with proteins that have little or no af...

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Activation of transcription by the promoterspecific factor Spl requires coactivators that are tightly associated with the TATA-box-binding protein (TBP) in the TFIID complex. Recent work has shown that the two glutamine-rich activation domains of Spl, A and B, can interact with at least one component of this complex, the TBP-associated factor dTAFH110. Here we report the mapping ofa region of Spl with alternating glutamine and hydrophobic residues which is required for the interaction with dTAFI11O and is important for mediating transcriptional activation. Substitution of bulky hydrophobic residues within this region decreased both interaction with dTAFI11O and transcriptional activation in Drosophika cels. In contrast, mutation ofglutamine residues in this region had no effect. Thus, the strength of the Spl-TAF interaction correlates with the potency of Spl as a transcriptional activator, indicating that this activator-TAF interaction is an important part of the mechanism of btanscriptional activation.,Sequence comparison of three activation domains shown to bind dTAFIl1O suggests that different activators that utilize dTAF]m11O as a coactivator may share common sequence features that we have determined to be important for the Spl-dTAFIl110 interaction.Transcription initiation by RNA polymerase II requires a number of accessory factors,

The yeast transcriptional activator GAL4 binds specific sites on DNA to activate transcription of adjacent genes. The distinct activating regions of GAL4 are rich in acidic residues and it has been suggested that these regions interact with another protein component of the transcriptional machinery (such as the TATA-binding protein or RNA polymerase II) while the DNA-binding region serves to position the activating region near the gene. Here we show that various GAL4 derivatives, when expressed at high levels in yeast, inhibit transcription of certain genes lacking GAL4 binding sites, that more efficient activators inhibit more strongly and that inhibition does not depend on the DNA-binding domain. We suggest that this inhibition, which we call squelching, reflects titration of a transcription factor by the activating region of GAL4.