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SUMO and Ubiquitin in the Nucleus: Different Functions, Similar Mechanisms?

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SUMO and Ubiquitin in the Nucleus: Different Functions, Similar Mechanisms? Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Grace Gill1 Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA The small ubiquitin-related modifier SUMO posttrans- tin, SUMO modification regulates protein localization lationally modifies many proteins with roles in diverse and activity. processes including regulation of transcription, chroma- This review focuses on recent advances in our under- tin structure, and DNA repair. Similar to nonproteolytic standing of SUMO function and regulation, drawing on a roles of ubiquitin, SUMO modification regulates protein limited set of examples relating to gene expression, chro- localization and activity. Some proteins can be modified matin structure, and DNA repair. Comparison of SUMO by SUMO and ubiquitin, but with distinct functional and ubiquitin activities in the nucleus reveals interest- consequences. It is possible that the effects of ubiquiti- ing differences in function and suggests surprising simi- nation and SUMOylation are both largely due to binding larities in mechanism. Thus, for example, modification of proteins bearing specific interaction domains. Both of transcription factors and histones by ubiquitin is gen- modifications are reversible, and in some cases dynamic erally associated with increased gene expression whereas cycles of modification may be required for activity. Stud- modification of transcription factors and histones by ies of SUMO and ubiquitin in the nucleus are yielding SUMO is generally associated with decreased gene ex- new insights into regulation of gene expression, genome pression. In some cases, SUMO and ubiquitin may di- maintenance, and signal transduction. rectly compete for modification of target lysines. Despite the different functional consequences associated with Reversible posttranslational modifications are widely these modifications, current data supports the hypoth- used to dynamically regulate protein activity. Proteins esis that SUMO, like ubiquitin, largely functions to pro- can be modified by small chemical groups, sugars, lipids, mote interactions with proteins that have little or no and even by covalent attachment of other polypeptides. affinity for the unmodified substrate. Both SUMOylation The most well-known example of a polypeptide modifier and ubiquitination are reversible, and, in some cases, is ubiquitin. Posttranslational modification by ubiquitin dynamic cycles of conjugation/deconjugation may be re- plays a central role in targeting proteins for proteolytic quired for regulated activity. Advances in understanding degradation by the proteasome, although covalent at- the nonproteolytic roles of SUMO and ubiquitin in the tachment of ubiquitin to proteins can also regulate lo- nucleus are yielding new insights into regulation of fun- calization and/or activity independent of proteolysis. In damental cellular processes. addition to ubiquitin, there are several ubiquitin-like proteins (UbLs) that can also be conjugated to, and alter SUMO is structurally related to ubiquitin the function of, substrate proteins. One Ubl in particu- lar, the small ubiquitin-related modifier (SUMO) has Compared to posttranslational modifiers such as a phos- been shown to covalently modify a large number of pro- phate or acetyl group, ubiquitin and ubiquitin-related teins with important roles in many cellular processes proteins are structurally complex. Specific surface resi- including gene expression, chromatin structure, signal dues of ubiquitin participate in different ubiquitin- transduction, and maintenance of the genome. The en- dependent interactions such as binding to the protea- zymatic machinery that adds and removes SUMO is some or components of the endocytic machinery (Sloper- similar to, but distinct from, the ubiquitination machin- Mould et al. 2001). NMR studies have shown that ery. Posttranslational modification by SUMO has not SUMO-1, which is 18% identical to ubiquitin, has a simi- been generally associated with increased protein degra- lar protein fold (Fig. 1; Bayer et al. 1998). Importantly, de- dation. Rather, similar to nonproteolytic roles of ubiqui- spite the similar protein fold, the distribution of charged residues on the surface of SUMO is very different from that of ubiquitin or other UbLs. In addition, SUMO has an N- [Keywords: SUMO; ubiquitin; transcription; DNA repair; chromatin; nucleus] terminal extension not found in ubiquitin. These differ- 1Correspondence. ences likely account for the finding that distinct enzymes E-MAIL [email protected]; FAX (617) 432-6225. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ mediate SUMO conjugation and deconjugation as well as gad.1214604. the unique activities attributed to SUMO. 2046 GENES & DEVELOPMENT 18:2046–2059 © 2004 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/04; www.genesdev.org Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press SUMO and ubiquitin in the nucleus Figure 1. SUMO is highly related to ubiquitin. (A) Amino acid sequence alignments of ubiquitin and the four SUMO homologs from human. Identities are indicated in bold and similarities are shaded. A consensus motif for SUMOylation present in SUMO-2, SUMO-3, and SUMO-4 is boxed in yellow; the SUMO acceptor lysine (K) in this motif is boxed in red. Ubiquitin Lys 48 and Lys 63, which serve as common sites for ubiquitin polymerization, are boxed in red. The site of cleavage to produce the mature proteins with C-terminal glycine–glycine residues is also indicated. A polymorphism at position 55 in SUMO-4 (M55V) has been described in the human population (Bohren et al. 2004). (B) Ribbon diagrams highlight the similarity of the three-dimensional structures of SUMO-1 and ubiquitin (Bayer et al. 1998). Secondary structure elements are indicated: ␤ sheets are green and ␣ helices are red. Notably, SUMO has an N-terminal extension not found in ubiquitin. Adapted with permission from a drawing by Peter Bayer (Bayer et al. 1998; © 1998 Journal of Molecular Biology). Four SUMO homologs have been described in mam- chains at least four subunits long. In contrast, SUMO is mals. SUMO-1 and SUMO-2/3 appear to modify both generally thought to function as a monomer. SUMO-1, common and different substrates. Thus, some substrates SUMO-2 and SUMO-3, have been observed to form poly- may be simultaneously modified by SUMO-1 and meric chains in vitro; however, the functional signifi- SUMO-2 whereas RanGAP1, for example, is predomi- cance, if any, of SUMO chains in vivo has not been es- nately modified by SUMO-1 and Topoisomerase II is pre- tablished (Johnson and Gupta 2001; Tatham et al. 2001; dominantly modified by SUMO-2/3 (Saitoh and Hinchey Pichler et al. 2002). Monomeric SUMO provides all es- 2000; Azuma et al. 2003; Vertegaal et al. 2004; Zhao et al. sential functions in yeast, as a mutant form of yeast 2004). The recently described SUMO-4 has a restricted SUMO lacking the major SUMO acceptor lysines is able pattern of expression with highest levels reported in the to support yeast viability (Bylebyl et al. 2003). Interest- kidney (Bohren et al. 2004). Currently, the mechanisms ingly, a mutant form of SUMO-2 lacking the major site that determine selective modification by specific SUMO of SUMOylation differs from wild-type SUMO-2 in its isoforms are not known, and the functional significance ability to influence production of Amyloid ␤ peptide of modification by specific SUMO isoforms also remains when overexpressed (Li et al. 2003). Thus, it remains to be determined. possible that polymerization or other posttranslational The ability of ubiquitin to form polymeric chains, modifications of SUMO may add complexity to SUMO where two or more ubiquitins are covalently attached to function in mammalian cells. one another, is critical for many biological activities of ubiquitin. Polymeric ubiquitin is structurally and func- The SUMOylation machinery tionally diverse because multiple lysines in Ub can each serve as a site of ubiquitin attachment. The well-known There are striking similarities between the machinery ability of ubiquitin to interact with the proteasome, for that attaches SUMO to substrate proteins and the en- example, is largely a property of Lys 48-linked ubiquitin zymes that participate in ubiquitination (Fig. 2; Pickart GENES & DEVELOPMENT 2047 Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Gill Figure 2. The SUMO conjugation pathway. The SUMO precursor is cleaved by SUMO-specific proteases (SENPs) with C-terminal hydrolase activity to expose a C-terminal glycine–glycine. In an ATP-dependent reaction, mature SUMO forms a thioester conjugate with the heterodimeric SUMO E1 activating enzyme Aos1/Uba2. SUMO is then transferred to the SUMO E2 conjugating enzyme Ubc9, with which it also forms a thioester intermediate. From Ubc9, SUMO is conjugated to a substrate protein via an isopeptide bond with a lysine residue (K). Several unrelated SUMO E3 ligases have been shown to stimulate transfer of SUMO from Ubc9 to specific substrates. SUMO E3 ligases may function as single polypeptides or as multiprotein complexes (see text). SUMO modification is reversible and SUMO is removed from substrates by SUMO-specific proteases (SENPs) with isopeptidase activity. 2001; K.I. Kim et al. 2002). Ubiquitin and SUMO
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