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Expression of inflammatory genes is determined in part by post-transcriptional regulation of mRNA metabolism but how stimulus- and transcript-dependent nuclear export influence is poorly understood. Here, we report a novel pathway in which LPS/TLR4 engagement promotes nuclear localization of IRAK2 to facilitate nuclear export of a specific subset of inflammation-related mRNAs for translation in murine macrophages. IRAK2 kinase activity is required for LPS-induced RanBP2-mediated IRAK2 sumoylation and subsequent nuclear translocation. Array analysis showed that an SRSF1-binding motif is enriched in mRNAs dependent on IRAK2 for nuclear export. Nuclear IRAK2 phosphorylates SRSF1 to reduce its binding to target mRNAs, which promotes the RNA binding of the nuclear export adaptor ALYREF and nuclear export receptor Nxf1 loading for the export of the mRNAs. In summary, LPS activates a nuclear function of IRAK2 that facilitates the assembly of nuclear export machinery to export selected inflammatory mRNAs to the cytoplasm for translation.

The RanGTPase activating protein RanGAP1 has essential functions in both nucleocytoplasmic transport and mitosis. In interphase, a significant fraction of vertebrate SUMO1-modified RanGAP1 forms a stable complex with the nucleoporin RanBP2/Nup358 at nuclear pore complexes. RanBP2 not only acts in the RanGTPase cycle but also is a SUMO1 E3 ligase. Here, we show that RanGAP1 is phosphorylated on residues T409, S428, and S442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. Nocodazole arrest leads to quantitative phosphorylation. The M-phase kinase cyclin B/Cdk1 phosphorylates RanGAP1 efficiently in vitro, and T409 phosphorylation correlates with nuclear accumulation of cyclin B1 in vivo. We find that phosphorylated RanGAP1 remains associated with RanBP2/Nup358 and the SUMO E2-conjugating enzyme Ubc9 in mitosis, hence mitotic phosphorylation may have functional consequences for the RanGTPase cycle and/or for RanBP2-dependent sumoylation.

Small ubiquitin-related modifier (SUMO) proteins are reversibly coupled to numerous intracellular targets and modulate their interactions, localization, activity or stability. Recent advances in the SUMO field have uncovered the first SUMO E3 ligases and point to a complex family of isopeptidases. SUMO has been linked to many different pathways, including nucleocytoplasmic transport. Modifying enzymes and an isopeptidase have been detected at nuclear pore complexes. In addition, studies in yeast suggest a requirement of SUMO conjugation for nuclear protein import, and specific SUMO targets depend on modification for nuclear import or export.

Research has been conducted on the Wnt-responsive transcription factor lymphoid enhancer factor 1 (LEF1) which activates transcription in association with beta-catenin and represses transcription in association with Groucho. The additional regulatory mechanisms of the LEF1 function have been investigated via the identified as an interaction partner of LEF1 protein which inhibits the activated signal transducers and activators of transcription and protein inhibitor of activated STAT, and the details are reported.

SUMO-1, a novel peptide of 101 amino acids, has been found to be covalently linked to the mammalian Ran GTPase-activating protein RanGAP1 in an adenosine triphosphate-dependent reaction. SUMO-1 exhibits a homology to ubiquitin, a 76-residue protein found in eukaryotes. Data indicate that the polypeptide is involved in protein targeting and not degradation. At least three additional intranuclear proteins are modified with SUMO-1 or with a protein closely resembling it.

Microtubule depolymerases of the kinesin‐13 family play important roles in various cellular processes and are frequently overexpressed in different cancer types. Despite the importance of their correct abundance, remarkably little is known about how their levels are regulated in cells. Using comprehensive screening on protein microarrays, we identified 161 candidate substrates of the multi‐subunit ubiquitin E3 ligase SCFFbxw5, including the kinesin‐13 member Kif2c/MCAK. In vitro reconstitution assays demonstrate that MCAK and its closely related orthologs Kif2a and Kif2b become efficiently polyubiquitylated by neddylated SCFFbxw5 and Cdc34, without requiring preceding modifications. In cells, SCFFbxw5 targets MCAK for proteasomal degradation predominantly during G2. While this seems largely dispensable for mitotic progression, loss of Fbxw5 leads to increased MCAK levels at basal bodies and impairs ciliogenesis in the following G1/G0, which can be rescued by concomitant knockdown of MCAK, Kif2a or Kif2b. We thus propose a novel regulatory event of ciliogenesis that begins already within the G2 phase of the preceding cell cycle. SYNOPSIS: Despite their importance in normal cellular physiology and tumorigenesis, regulation of microtubule depolymerases remains little understood. Here, the kinesin‐13 family member MCAK is found to be ubiquitylated and degraded via SCFFbxw5 to facilitate ciliogenesis. SCFFbxw5 modifies kinesin‐13 proteins with K48‐linked polyubiquitin chains.SCFFbxw5‐dependent polyubiquitylation targets MCAK for degradation during G2 phase, while post‐mitotic degradation is driven by the APC/C ligase.Defects in MCAK ubiquitylation and degradation cause its accumulation at basal bodies during the subsequent G1/G0 phase, impairing ciliogenesis. [ABSTRACT FROM AUTHOR]

GTPase Ran is a low molecular weight cytosolic factor activated by the protein Ran. Light and electron immunolocalization showed that Ran localizes at the cytoplasmic surface of the nuclear pore complex during nuclear protein import in the presence of nonhydrolyzable analogs of GTP. Binding studies showed that Ran-GTP binds with a pore complex protein. Blot overlay techniques identified this protein to be the 358-kD protein RanBP2. It is suggested that RAN-GTP binding to the nuclear pore complex occurs at or near the region where RanBP2 localizes.

Is SUMO unique in the way it regulates proteins? No. SUMOylation is one of many types of modification that can change and regulate the function of a protein. Such modifications [...]

Molecular switches are essential modules in signaling networks and transcriptional reprogramming. Here, we describe a role for small ubiquitin‐related modifier SUMO as a molecular switch in epidermal growth factor receptor (EGFR) signaling. Using quantitative mass spectrometry, we compare the endogenous SUMO proteomes of HeLa cells before and after EGF stimulation. Thereby, we identify a small group of transcriptional coregulators including IRF2BP1, IRF2BP2, and IRF2BPL as novel players in EGFR signaling. Comparison of cells expressing wild type or SUMOylation‐deficient IRF2BP1 indicates that transient deSUMOylation of IRF2BP proteins is important for appropriate expression of immediate early genes including dual specificity phosphatase 1 (DUSP1, MKP‐1) and the transcription factor ATF3. We find that IRF2BP1 is a repressor, whose transient deSUMOylation on the DUSP1 promoter allows—and whose timely reSUMOylation restricts—DUSP1 transcription. Our work thus provides a paradigm how comparative SUMO proteome analyses serve to reveal novel regulators in signal transduction and transcription. SYNOPSIS: Transcriptional repressors of the IRF2BP family and SUMO play a critical role in EGFR signaling. Transient de‐SUMOylation of IRF2BP proteins in response to EGF contributes to immediate early gene transcription. EGF induces rapid and transient deSUMOylation of five transcriptional regulators.DeSUMOylation of IRF2BP proteins upon EGF treatment enhances the transcriptional response of immediate early genes.Loss of IRF2BP1/2 leads to elevated EGFR expression and enhanced cell proliferation. [ABSTRACT FROM AUTHOR]

Abstract Post-translational modifiers of the SUMO (Small Ubiquitin-related Modifier) family have emerged as key regulators of protein function and fate. While the past few years have seen an enormous increase in knowledge on SUMO enzymes, substrates, and consequences of modification, regulation of SUMO conjugation is far from being understood. This brief review will provide an overview on recent advances concerning (i) the interplay between sumoylation and other post-translational modifications at the level of individual targets and (ii) global regulation of SUMO conjugation and deconjugation.

Abstract Reversible post-translational modifications (PTMs) ensure rapid signal transmission from sensors to effectors. Reversible modification of proteins by the small proteins Ubiquitin and SUMO are involved in virtually all cellular processes and can modify thousands of proteins. Ubiquitination or SUMOylation is the reversible attachment of these modifiers to lysine residues of a target via isopeptide bond formation. These modifications require ATP and an enzymatic cascade composed of three classes of proteins: E1 activating enzymes, E2 conjugating enzymes and E3 ligases. The reversibility of the modification is ensured by specific isopeptidases. E1 and E2 enzymes, some E3 ligases and most isopeptidases have catalytic cysteine residues, which make them potentially susceptible for oxidation. Indeed, an increasing number of examples reveal regulation of ubiquitination and SUMOylation by reactive oxygen species, both in the context of redox signaling and in severe oxidative stress. Importantly, ubiquitination and SUMOylation play essential roles in the regulation of ROS homeostasis, participating in the control of ROS production and clearance. In this review, we will discuss the interplay between ROS homeostasis, Ubiquitin and SUMO pathways and the implications for the oxidative stress response and cell signaling. [ABSTRACT FROM AUTHOR]

To sense and defend against oxidative stress, cells depend on signal transduction cascades involving redox-sensitive proteins. We previously identified SUMO (small ubiquitin-related modifier) enzymes as downstream effectors of reactive oxygen species ( ROS). Hydrogen peroxide transiently inactivates SUMO E1 and E2 enzymes by inducing a disulfide bond between their catalytic cysteines. How important their oxidation is in light of many other redox-regulated proteins has however been unclear. To selectively disrupt this redox switch, we identified a catalytically fully active SUMO E2 enzyme variant (Ubc9 D100A) with strongly reduced propensity to maintain a disulfide with the E1 enzyme in vitro and in cells. Replacement of Ubc9 by this variant impairs cell survival both under acute and mild chronic oxidative stresses. Intriguingly, Ubc9 D100A cells fail to maintain activity of the ATM-Chk2 DNA damage response pathway that is induced by hydrogen peroxide. In line with this, these cells are also more sensitive to the ROS-producing chemotherapeutic drugs etoposide/Vp16 and Ara-C. These findings reveal that SUMO E1~E2 oxidation is an essential redox switch in oxidative stress. [ABSTRACT FROM AUTHOR]

Differentiation and dedifferentiation, accompanied by proliferation play a pivotal role for the phenotypic development of vascular proliferative diseases (VPD), such as restenosis. Increasing evidence points to an essential role of regulated nucleoporin expression in the choice between differentiation and proliferation. However, whether components of the Ran GTPase cycle, which is of pivotal importance for both nucleocytoplasmic transport and for mitotic progression, are subject to similar regulation in VPD is currently unknown. Here, we show that differentiation of human coronary artery smooth muscle cell (CASMC) to a contractile phenotype by stepwise serum depletion leads to significant reduction of RanGAP1 protein levels. The inverse event, dedifferentiation of cells, was assessed in the rat carotid artery balloon injury model, a well-accepted model for neointima formation and restenosis. As revealed by temporospatial analysis of RanGAP1 expression, neointima formation in rat carotid arteries was associated with a significant upregulation of RanGAP1 expression at 3 and 7 days after balloon injury. Of note, neointimal cells located at the luminal surface revealed persistent RanGAP1 expression, as opposed to cells in deeper layers of the neointima where RanGAP1 expression was less or not detectable at all. To gain first evidence for a direct influence of RanGAP1 levels on differentiation, we reduced RanGAP1 in human coronary artery smooth muscle cells by siRNA. Indeed, downregulation of the essential RanGAP1 protein by 50% induced a differentiated, spindle-like smooth muscle cell phenotype, accompanied by an upregulation of the differentiation marker desmin. Reduction of RanGAP1 levels also resulted in a reduction of mitogen induced cellular migration and proliferation as well as a significant upregulation of the cyclin-dependent kinase inhibitor p27KIP1, without evidence for cellular necrosis. These findings suggest that RanGAP1 plays a critical role in smooth muscle cell differentiation, migration and proliferation in vitro and in vivo. Appropriate modulation of RanGAP1 expression may thus be a strategy to modulate VPD development such as restenosis. [ABSTRACT FROM AUTHOR]

Posttranslational modification with small ubiquitin-related modifier (SUMO) proteins is now established as one of the key regulatory protein modifications in eukaryotic cells. Hundreds of proteins involved in processes such as chromatin organization, transcription, DNA repair, macromolecular assembly, protein homeostasis, trafficking, and signal transduction are subject to reversible sumoylation. Hence, it is not surprising that disease links are beginning to emerge and that interference with sumoylation is being considered for intervention. Here, we summarize basic mechanisms and highlight recent developments in the physiology of sumoylation. [ABSTRACT FROM AUTHOR]

SUMOylation is an essential modification that regulates hundreds of proteins in eukaryotic cells. Owing to its dynamic nature and low steady-state levels, endogenous SUMOylation is challenging to detect. Here, we present a method that allows efficient enrichment and identification of endogenous targets of SUMO1 and the nearly identical SUMO2 and 3 (SUMO 2/3) from vertebrate cells and complex organ tissue. Using monoclonal antibodies for which we mapped the epitope, we enriched SUMOylated proteins by immunoprecipitation and peptide elution. We used this approach in combination with MS to identify SUMOylated proteins, which resulted in the first direct comparison of the endogenous SUMO1- and SUMO2/3-modified proteome in mammalian cells, to our knowledge. This protocol provides an affordable and feasible tool to investigate endogenous SUMOylation in primary cells, tissues and organs, and it will facilitate understanding of SUMO's role in physiology and disease. [ABSTRACT FROM AUTHOR]

Eps8, a bi-functional actin cytoskeleton remodeller, is a positive regulator of cell proliferation and motility. Here, we describe an unrecognized mechanism regulating Eps8 that is required for proper mitotic progression: whereas Eps8 is stable in G1 and S phase, its half-life drops sharply in G2. This requires G2-specific proteasomal degradation mediated by the ubiquitin E3 ligase SCFFbxw5. Consistent with a short window of degradation, Eps8 disappears from the cell cortex early in mitosis, but reappears at the midzone of dividing cells. Failure to reduce Eps8 levels in G2 prolongs its localization at the cell cortex and markedly delays cell rounding and prometaphase duration. However, during late stages of mitosis and cytokinesis, Eps8 capping activity is required to prevent membrane blebbing and cell-shape deformations. Our findings identify SCFFbxw5-driven fluctuation of Eps8 levels as an important mechanism that contributes to cell-shape changes during entry into-and exit from-mitosis. [ABSTRACT FROM AUTHOR]

SUMOylation, an essential posttranslational protein modification, is involved in many eukaryotic cellular signaling pathways. The identification of SUMOylated proteins is difficult, because SUMOylation sites in proteins are hard to predict, SUMOylated protein states are transient in vivo and labile in vitro, only a small substrate fraction is SUMOylated in vivo, and identification tools for natively SUMOylated proteins are rare. To solve these problems, we generated knock-in mice expressing His6-HA-SUMO1. By anti-HA immunostaining, we show that SUMO1 conjugates in neurons are only detectable in nuclei and annulate lamellae. By anti-HA affinity purification, we identified several hundred candidate SUMO1 substrates, of which we validated Smchd1, Ctip2, TIF1γ, and Zbtb20 as novel substrates. The knock-in mouse represents an excellent mammalian model for studies on SUMO1 localization and screens for SUMO1 conjugates in vivo. [ABSTRACT FROM AUTHOR]

Isopeptidases are essential regulators of protein ubiquitination and sumoylation. However, only two families of SUMO isopeptidases are at present known. Here, we report an activity-based search with the suicide inhibitor haemagglutinin (HA)-SUMO-vinylmethylester that led to the identification of a surprising new SUMO protease, ubiquitin-specific protease-like 1 (USPL1). Indeed, USPL1 neither binds nor cleaves ubiquitin, but is a potent SUMO isopeptidase both in vitro and in cells. C13orf22l-an essential but distant zebrafish homologue of USPL1-also acts on SUMO, indicating functional conservation. We have identified invariant USPL1 residues required for SUMO binding and cleavage. USPL1 is a low-abundance protein that colocalizes with coilin in Cajal bodies. Its depletion does not affect global sumoylation, but causes striking coilin mislocalization and impairs cell proliferation, functions that are not dependent on USPL1 catalytic activity. Thus, USPL1 represents a third type of SUMO protease, with essential functions in Cajal body biology. [ABSTRACT FROM AUTHOR]

BICD2 is one of the two mammalian homologues of the Drosophila Bicaudal D, an evolutionarily conserved adaptor between microtubule motors and their cargo that was previously shown to link vesicles and mRNP complexes to the dynein motor. Here, we identified a G2-specific role for BICD2 in the relative positioning of the nucleus and centrosomes in dividing cells. By combining mass spectrometry, biochemical and cell biological approaches, we show that the nuclear pore complex (NPC) component RanBP2 directly binds to BICD2 and recruits it to NPCs specifically in G2 phase of the cell cycle. BICD2, in turn, recruits dynein-dynactin to NPCs and as such is needed to keep centrosomes closely tethered to the nucleus prior to mitotic entry. When dynein function is suppressed by RNA interference-mediated depletion or antibody microinjection, centrosomes and nuclei are actively pushed apart in late G2 and we show that this is due to the action of kinesin-1. Surprisingly, depletion of BICD2 inhibits both dynein and kinesin-1-dependent movements of the nucleus and cytoplasmic NPCs, demonstrating that BICD2 is needed not only for the dynein function at the nuclear pores but also for the antagonistic activity of kinesin-1. Our study demonstrates that the nucleus is subject to opposing activities of dynein and kinesin-1 motors and that BICD2 contributes to nuclear and centrosomal positioning prior to mitotic entry through regulation of both dynein and kinesin-1. [ABSTRACT FROM AUTHOR]

Summary: Posttranslational modification with small ubiquitin-related modifier (SUMO) has emerged as a central regulatory mechanism of protein function. However, little is known about the regulation of sumoylation itself. It has been reported that it is increased after exposure to various stresses including strong oxidative stress. Conversely, we report that ROS (reactive oxygen species), at low concentrations, result in the rapid disappearance of most SUMO conjugates, including those of key transcription factors. This is due to direct and reversible inhibition of SUMO conjugating enzymes through the formation of (a) disulfide bond(s) involving the catalytic cysteines of the SUMO E1 subunit Uba2 and the E2-conjugating enzyme Ubc9. The same phenomenon is also observed in a physiological scenario of endogenous ROS production, the respiratory burst in macrophages. Thus, our findings add SUMO conjugating enzymes to the small list of specific direct effectors of H2O2 and implicate ROS as key regulators of the sumoylation-desumoylation equilibrium. [Copyright &y& Elsevier]

Post-translational modification with small ubiquitin-related modifier (SUMO) alters the function of many proteins, but the molecular mechanisms and consequences of this modification are still poorly defined. During a screen for novel SUMO1 targets, we identified the ubiquitin-conjugating enzyme E2-25K (Hip2). SUMO attachment severely impairs E2-25K ubiquitin thioester and unanchored ubiquitin chain formation in vitro. Crystal structures of E2-25K(1-155) and of the E2-25K(1-155)-SUMO conjugate (E2-25K*SUMO) indicate that SUMO attachment interferes with E1 interaction through its location on the N-terminal helix. The SUMO acceptor site in E2-25K, Lys14, does not conform to the consensus site found in most SUMO targets (?KXE), and functions only in the context of ana-helix. In contrast, adjacent SUMO consensus sites are modified only when in unstructured peptides. The demonstration that secondary structure elements are part of SUMO attachment signals could contribute to a better prediction of SUMO targets. [ABSTRACT FROM AUTHOR]

The tumor suppressor, Smad4/DPC4, is a common signal transducer in transforming growth factor-β (TGF-β) signaling. In this study, we demonstrated that the protein inhibitor of activated STAT1 (PIAS1) regulates the signaling potential of Smad4 through a sumoylation-dependent mechanism. PIAS1 was shown to be an E3 ligase for Smad4 sumoylation in vitro and in vivo. PIAS1 physically interacted with Smad4 in a TGF-β-inducible manner. A minimal SUMO E3 ligase domain and Smad4binding domain were defined on PIAS1 protein. The RING finger domain of PIAS1 was essential for its E3 ligase function. Although PIAS1 enhanced the Smad4dependent transcriptional activation of TGF-β signaling, a mutant lacking the RING domain inhibited the sumoylation of Smad4 in a dominant negative manner and, as a result, abolished the transcriptional response of TGF-β. These data demonstrate that PIAS1 protein positively modulates TGF-β responses as a SUMO E3 ligase for Smad4. [ABSTRACT FROM AUTHOR]

Sp3 is a ubiquitous transcription factor closely related to Sp1. Here we show that Sp3 is a target for SUMO modification in vivo and in vitro. SUMO modification of Sp3 occurs at a single lysine located between the second glutamine-rich activation domain and the DNA-binding domain. Mutational analyses identified the sequence IKXE as essential for SUMO conjugation to Sp3. We identified the protein inhibitor of activated STAT1 (PIAS1) as an interaction partner of Sp3 and Ubc9. Moreover, PIAS1 strongly stimulated SUMO conjugation to Sp3, thus acting as an E3 ligase for SUMO conjugation to Sp3. All mutations that prevented SUMO modification in vitro strongly enhanced the transcriptional activity of Sp3, showing that SUMO modification silences Sp3 activity. SUMO-modified Sp3 bound to DNA with similar specificity and affinity as unmodified Sp3. However, DNA-bound Sp3 did not act as a substrate for SUMO modification. [ABSTRACT FROM AUTHOR]

Transcriptional repression mediated through histone deacetylation is a critical component of eukaryotic gene regulation. Here we demonstrate that the class II histone deacetylase HDAC4 is covalently modified by the ubiquitin‐related SUMO‐1 modifier. A sumoylation‐deficient point mutant (HDAC4‐K559R) shows a slightly impaired ability to repress transcription as well as reduced histone deacetylase activity. The ability of HDAC4 to self‐aggregate is a prerequisite for proper sumoylation in vivo. Calcium/calmodulin‐dependent protein kinase (CaMK) signalling, which induces nuclear export, abrogates SUMO‐1 modification of HDAC4. Moreover, the modification depends on the presence of an intact nuclear localization signal and is catalysed by the nuclear pore complex (NPC) RanBP2 protein, a factor newly identified as a SUMO E3 ligase. These findings suggest that sumoylation of HDAC4 takes place at the NPC and is coupled to its nuclear import. Finally, modification experiments indicate that the MEF2‐interacting transcription repressor (MITR) as well as HDAC1 and ‐6 are similarly SUMO modified, indicating that sumoylation may be an important regulatory mechanism for the control of transcriptional repression mediated by both class I and II HDACs. [ABSTRACT FROM AUTHOR]

SUMO (small ubiquitin-related modifier) is the best-characterized member of a growing family of ubiquitin-related proteins. It resembles ubiquitin in its structure, its ability to be ligated to other proteins, as well as in the mechanism of ligation. However, in contrast to ubiquitination—often the first step on a one-way road to protein degradation—SUMOlation does not seem to mark proteins for degradation. In fact, SUMO may even function as an antagonist of ubiquitin in the degradation of selected proteins. While most SUMO targets are still at large, available data provide compelling evidence for a role of SUMO in the regulation of protein-protein interactions and/or subcellular localization. [ABSTRACT FROM AUTHOR]

A paper in the August 9 issue of Cell describes a novel role for the nucleoporin Npap60/Nup50 as a soluble cofactor in importin-α:β-mediated nuclear protein import. These findings add a new dimension of complexity to the current understanding of protein transport pathways. [Copyright &y& Elsevier]

The heat shock response is a transcriptional program of organisms to counteract an imbalance in protein homeostasis. It is orchestrated in all eukaryotic cells by heat shock transcription factor 1 (Hsf1). Despite very intensive research, the intricacies of the Hsf1 activation-attenuation cycle remain elusive at a molecular level. Post-translational modifications belong to one of the key mechanisms proposed to adapt the Hsf1 activity to the needs of individual cells, and phosphorylation of Hsf1 at multiple sites has attracted much attention. According to cell biological and proteomics data, Hsf1 is also modified by small ubiquitin-like modifier (SUMO) at several sites. How SUMOylation affects Hsf1 activity at a molecular level is still unclear. Here, we analyzed Hsf1 SUMOylation in vitro with purified components to address questions that could not be answered in cell culture models. In vitro Hsf1 is primarily conjugated at lysine 298 with a single SUMO, though we did detect low-level SUMOylation at other sites. Different SUMO E3 ligases such as protein inhibitor of activated STAT 4 enhanced the efficiency of in vitro modification but did not alter SUMO site preferences. We provide evidence that Hsf1 trimerization and phosphorylation at serines 303 and 307 increases SUMOylation efficiency, suggesting that Hsf1 is SUMOylated in its activated state. Hsf1 can be SUMOylated when DNA bound, and SUMOylation of Hsf1 does neither alter DNA-binding affinity nor affects heat shock cognate 71kDa protein (HSPA8)+DnaJ homolog subfamily B member 1-mediated monomerization of Hsf1 trimers and concomitant dislocation from DNA. We propose that SUMOylation acts at the transcription level of the heat shock response. [ABSTRACT FROM AUTHOR]