You are on page 1of 4


Minireview Vol. 279, No. 52, Issue of December 24, pp. 53899 –53902, 2004
© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.
Printed in U.S.A.

SUMO-activating (E1) enzyme is a heterodimer consisting of Aos1

Regulation and Function of and Uba2 (also known as SAE1/SAE2 or Sua1/hUba2 in humans).
SUMO Modification* Activation of SUMO by the E1 is an ATP-dependent process and
results in the formation of a thioester bond between SUMO and the
Uba2 subunit of the E1-activating enzyme. Activation is followed
Published, JBC Papers in Press, September 24, 2004, by transfer of SUMO from the E1 enzyme to a conserved cysteine in
DOI 10.1074/jbc.R400021200
the conjugating (E2) enzyme, Ubc9. This single E2 enzyme identi-
Roland S. Hilgarth‡, Lynea A. Murphy‡§, fied so far for the sumoylation pathway contrasts with the multiple
Hollie S. Skaggs‡§, Donald C. Wilkerson‡, E2 enzymes involved in attaching ubiquitin to proteins (4, 10).
Hongyan Xing‡, and Kevin D. Sarge‡¶ The final step of sumoylation involves ligation of SUMO to the
From the ‡Department of Molecular and Cellular target protein. Until recently there was speculation as to whether
Biochemistry and §Graduate Center for Toxicology, SUMO ligation to target proteins involved E3 ligase-like proteins

Downloaded from at LIFE SCIENCE LIBRARY, ACADEMIA SINICA on August 28, 2006
University of Kentucky, Lexington, Kentucky 40536 such as are required for ubiquitination. However, it is now clear
that such E3 ligases do exist for the SUMO-1 modification pathway
Small ubiquitin-like modifier (SUMO)1 is a protein of 97 amino and that they play important roles in modulating the efficiency of
acids that is structurally similar to ubiquitin and has been called SUMO attachment to target proteins (2). As with the ubiquitin
by other names including Smt3p, Pmt2p, PIC-1, GMP1, Ubl1, and system, SUMO E3 proteins are defined by three characteristics:
Sentrin (1). Like ubiquitin, SUMO has been found to be covalently binding to the substrate protein either directly or indirectly, bind-
attached to certain lysine residues of specific target proteins (2). In ing to the E2 conjugation enzyme, and the ability to stimulate
contrast to ubiquitination, however, sumoylation does not promote transfer of the modifier to the substrate or to another modifier in
the degradation of proteins but instead alters a number of different the case of modifier chain formation. Three different general types
functional parameters of proteins, depending on the protein sub- of SUMO E3 ligases have been described (11–16). The first E3
strate in question. These parameters include but are not limited to group comprises the PIAS family of proteins. In yeast only two E3
properties such as subcellular localization, protein partnering, and proteins have been identified (Siz1 and Siz2) which have sequence
DNA-binding and/or transactivation functions of transcription fac- similarity to mammalian PIAS proteins, of which at least five
tors (2– 4). The contrast between the functional effects of ubiquiti- members have SUMO E3 activity (11, 12, 14, 17). These proteins
nation and sumoylation is most striking in the case of I␬B, where share a common RING finger-like structure and bind directly to the
sumoylation stabilizes the protein by modifying the same residue Ubc9 E2 enzyme and some SUMO protein targets. This RING
that is ubiquitinated, thereby directly competing with that path- finger motif has also been identified in some of the ubiquitin E3
way (5). This review will focus on the regulation of SUMO modifi- ligases (18). A second type of SUMO E3 protein found in mamma-
cation and its role in controlling the functional properties of pro- lian systems is RanBP2, which is part of the nuclear pore complex
teins. The reader is also referred to other excellent reviews on this (15). RanBP2 differs from the PIAS proteins in that it does not have
topic (2– 4, 6 – 8). a RING finger domain or homology to ubiquitin E3 proteins. How-
ever, it interacts with Ubc9 although not the sumoylation target
Enzymology and Regulation of SUMO Conjugation protein (15). The final E3 protein type (Pc2) belongs to the Poly-
and Deconjugation comb protein family and stimulates sumoylation of C terminus
Three different ubiquitous SUMO-related proteins have been binding protein (16). In some cases sumoylation can exist in the
identified in mammalian cells, SUMO-1, SUMO-2, and SUMO-3, form of polymeric chains because the SUMO-1 paralogs SUMO-2
with SUMO-2 and SUMO-3 having greater sequence relatedness and SUMO-3 have internal SUMO modification consensus sites
with each other than with SUMO-1 (3, 4). Recently a tissue-specific that allow the formation of polymeric SUMO chains on modified
SUMO-4 has been identified in human kidney with homology to proteins (19). Other post-translational modifications can regulate the
SUMO-2/3, which raises the possibility that some SUMO proteins SUMO modification of a protein. For example, phosphorylation neg-
could have tissue-dependent functions (9). SUMO modification oc- atively regulates the sumoylation of several substrate proteins, in-
curs on the lysine in the consensus sequence ⌿KXE (where ⌿ cluding c-Jun, promyelocytic leukemia (PML), and I␬B␣, (2, 3). Phos-
represents a hydrophobic amino acid, and X represents any amino phorylation can also act positively, as in the case of the transcription
acid) (2, 3). The mechanism involved in maturation and transfer of factor HSF1 where sumoylation is stimulated by phosphorylation of
SUMO to target substrates is very similar to that seen with ubiq- serine residues near the SUMO modification site (20, 21).
uitination and other ubiquitin-like proteins (3, 4). This process As with other post-translational modifications, SUMO groups can
involves four enzymatic steps: maturation, activation, conjugation, be removed from proteins in a reaction catalyzed by SUMO-specific
and ligation (Fig. 1). In the first step the SUMO protein is cleaved proteases (2, 3). Some of these proteases have dual functionality in
by SUMO-specific carboxyl-terminal hydrolase to produce a carbox-
that they both process SUMO to its mature diglycine form and also
yl-terminal diglycine motif. This process of maturation is identical
cleave the isopeptide bond between SUMO and its target proteins (2).
with all three mammalian SUMO forms. After maturation, SUMO
In yeast, two SUMO proteases have been identified, Ulpl and Ulp2/
proteins are able to be utilized for conjugation to proteins. The
Smt4, both of which are specific for SUMO and display compartmen-
talization, with Ulp1 being present at the nuclear pore complex and
* This minireview will be reprinted in the 2004 Minireview Compendium, Upl2/Smt4 being present in the nucleoplasm. In mammals, several
which will be available in January, 2005. SUMO proteases have been confirmed with the possibility of many
¶ To whom correspondence should be addressed: Dept. of Molecular and
Cellular Biochemistry, University of Kentucky, 800 Rose St., Lexington, KY more being present due to alternative splice variants (2). As with
40536. Tel.: 859-323-5777; E-mail: yeast, many of the mammalian SUMO proteases are localized to
The abbreviations used are: SUMO, small ubiquitin-like modifier; E1,
ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin- different cellular compartments, which may function to regulate the
protein isopeptide ligase; PIAS, protein inhibitors of activated STATs; STAT, balance of protein sumoylation in these compartments.
signal transducer and activator of transcription; PML, promyelocytic leuke-
mia; NPC, nuclear pore complex; TGF-␤, transforming growth factor ␤; NB, Sumoylation and Subcellular Localization
nuclear body; AR, androgen receptor; GR, glucocorticoid receptor; PR, pro-
gesterone receptor; C/EBP, CCAAT enhancer-binding protein; SREBP, sterol Depending on the target protein, sumoylation can occur in the
regulatory element-binding protein; SRF, serum response factor; HDAC, cytoplasm or nucleus, and this modification is involved in regulat-
histone deacetylase; PCNA, proliferating cell nuclear antigen; EBV, Epstein-
Barr virus; HSF, heat shock factor; TCF, T-cell factor; LEF, lymphoid en- ing the subcellular localization of a number of substrate proteins.
hancer factor. RanGAP1 was the first identified SUMO substrate and plays an

This paper is available on line at 53899

53900 Minireview: Regulation and Function of SUMO Modification
form a stable trimeric complex (15, 32). This model is strengthened
by the observation that RanGAP1 is protected from SENP2 (SUMO
protease) degradation when found in this complex (15, 32). SENP2/
Axam itself associates with the nucleoplasmic face of the NPC via
its NH2-terminal domain (32, 34), and loss of this domain results in
relocalization of this enyzme and increased capacity for deconjuga-
tion of substrates (34). SENP2 also associates with Nup153, a
component of the nuclear basket in humans. Ulp1, the yeast ho-
mologue of the vertebrate SUMO isopeptidase SENP2, is required
for progression through the cell cycle and also localizes to the NPC
via the NH2-terminal domain, which appears to be necessary for
localization as well as enzymatic specificity (35). Further establish-
FIG. 1. The SUMO conjugation pathway. SUMO is cleaved into its ing the connection between sumoylation and nuclear import are
mature form by the SUMO protease Ulp1. After this step it is activated in an data showing that yeast Ulp1 and Ulp2 mutants, deficient in
ATP-dependent manner by conjugation to the Uba2 subunit of the E1-
activating heterodimer Aos1/Uba2. Following activation SUMO is trans- SUMO conjugation, display an impairment of classical nuclear
ferred to the E2-conjugating enzyme Ubc9. In the final step SUMO is trans- localization signal-mediated protein import (36).
ferred in a ligation reaction to substrate proteins forming an isopeptide bond
between the terminal glycine on SUMO and the ⑀-amino group of a lysine in Sumoylation is most often implicated in promoting localization

Downloaded from at LIFE SCIENCE LIBRARY, ACADEMIA SINICA on August 28, 2006
the target protein to be modified. This ligation reaction is aided by SUMO of proteins to the nucleus and in some cases to nuclear bodies.
ligase E3 proteins (E3), which can directly interact with target proteins or However, there is evidence that SUMO modification could also
the E2 enzyme.
function to regulate nuclear export of some substrates. For exam-
ple, nuclear sumoylation of Dictyostelium Mek1 is responsible for
important role in the regulation of transport of ribonucleoproteins its movement to the cytoplasm (37), and mutation of lysine 99 of the
and proteins across the NPC (22, 23). Unmodified RanGAP1 re- TEL protein leads to increased levels of this protein in the nucleus,
sides predominantly in the cytoplasm and upon conjugation with suggesting a possible role for sumoylation in its nuclear export (38).
SUMO associates with the cytoplasmic fibers of the NPC (22, 24). In addition, sumoylation of heterogeneous nuclear ribonucleopro-
SUMO modification directs RanGAP1 to the NPC by an interaction teins M and C has been proposed to function as a regulator of
with RanBP2/Nup358, possibly mediated by sumoylation-induced conformational changes that may influence nucleocytoplasmic
formation of a binding interface for interaction of these two pro-
transport of these protein complexes (39).
teins (25). Analysis of nuclear localization signal mutants of a
protein called Smad4, a factor with a major role in the TGF-␤ signal SUMO and Transcription Regulation
transduction pathway, indicates that nuclear import of this protein The sumoylation of transcription activators, repressors, coacti-
is required for it to be sumoylated (26). Smad4 moves to the nucleus vators, corepressors, and components of PML NBs is involved in
in response to TGF-␤ stimulation, and immunofluorescence analy-
the regulation of gene expression (3, 6, 8). The activities of many
sis of TGF-␤-induced cells that were SUMO-1 transfected demon-
transcription factors are regulated by association with PML NBs,
strated an increase in the nuclear localization of Smad4 (26).
and assembly of PML NBs requires sumoylation of the PML pro-
Nuclei contain a number of distinct bodies that are defined, at
tein (3, 7). Thus, alteration of PML sumoylation has broad effects
least in part, by the proteins contained in them. For example, the
on transcription (1, 7). For example, sumoylation of PML recruits
PML and Sp100 proteins are major components of PML nuclear
corepressor Daxx to PML NBs, thereby relieving Daxx-mediated
bodies (PML NBs), also called ND10. Sumoylation has been found
repression of these genes. Similarly, sumoylation of PML directs
to be required for the subcellular localization of some, but not all,
p53 to PML NBs and could then trigger some modification, such as
proteins found in bodies such as ND10. For example, the sumoylated
acetylation and sumoylation, which stimulates the transcriptional
forms of PML and Sp100 are found exclusively in the nucleus (27).
activity of p53. Also, sumoylation of PML recruits another sumoyl-
SUMO conjugation was determined to be essential for PML protein
ated nuclear body-associated protein, Sp100. Sumoylation of other
localization in ND10, whereas the targeting and accumulation of
Sp100 in these bodies was not sumoylation-dependent (27, 28). This transcription factors has also been found to regulate their localiza-
appears to be true for other SUMO substrates as well (p53, LEF1, tion, including Drosophila Dorsal, Bicoid, p73␣, and Pdx1 (1). Sim-
Daxx, and SRF1) which will localize to ND10 even after mutation of ilar to what is observed for PML, corepressor HIPK2 and repressor
their target lysine (3). Topors, a DNA topoisomerase I-binding pro- TEL and TEL-AML1 localize to nuclear dots in a SUMO-dependent
tein, interacts with both Ubc9 and SUMO-1 leading to the formation manner. Whether sumoylation alters the repressive function of
of Topors nuclear speckles with close association to ND10, although these transcription factors is unclear.
sumoylation-deficient mutants were still able to localize to the nu- The sumoylation of transcription factors has been reported to
clear speckles (29). SUMO modification also targets cellular localiza- have different effects on their activities in various pathways in-
tion of tumor suppressors TEL and Smad4, which in the case of TEL, cluding those involving cytokines, WNT, steroid hormone, and
a suspected tumor suppressor, leads to localization of this phospho- AP-1 (3, 6, 8). In most cases, SUMO modification plays a negative
protein in TEL bodies, a cell cycle-dependent nuclear structure (30). role in transcription regulation. The transcription factors that are
Sumoylation appears to also be important for localization of the inhibited by SUMO modification include STAT1, catenin-TCF/
transcription factor HSF1 to nuclear bodies (31). LEF, c-Jun, Ah receptor nuclear translocator (ARNT), CEBP␣,
An exciting development in understanding both the subcellular c-Myb, Sp3, IRF-1, SREBPs, SRF, Elk, AP1, AP2, androgen recep-
sites of sumoylation and the role of this modification in regulating tor (AR), glucocorticoid receptor (GR), and progesterone receptor
subcellular localization of proteins has been the discovery that (PR), as well as huntingtin (3, 6, 40). The ⌿KXE sumoylation site
components of the sumoylation machinery are localized at the motifs of some factors such as GR, Sp3, c-Myb, C/EBP, and the
nuclear pore complex (32, 33). This localization suggests that SREBPs are located within an inhibitory or negative regulatory
sumoylation of at least some proteins occurring as they enter the domain or the so-called “synergy control” motifs that can transre-
nucleus could be involved in nuclear import itself or perhaps re- press transcriptional activity. Mutation of sumoylation sites in
tention of these proteins in the nucleus. For example, Nup358, a transcription factors has been found to increase their transcrip-
nuclear pore protein demonstrated to have SUMO E3 ligase activ- tional activity, for example, transcription factors Elk-1, Sp-3,
ity, localizes predominantly to the cytoplasmic filaments of the SREBPs, STAT-1, SRF, c-Myb, C/EBPs, AR, p300, c-Jun, GR, and
NPC and regulates targeting of RanGAP1 to the NPC (2, 25). Other peroxisome proliferator-activated receptor ␥ that may reflect a role
SUMO enzymes, Ubc9 and SENP2, have also been found to localize for SUMO-1 modification as a negative regulator of transactivation
at the nuclear pore. Ubc9, the E2 conjugating enzyme for SUMO, domains (3, 6, 41). Consistent with this idea, overexpression of free
localizes to the cytoplasmic and nucleoplasmic faces of the NPC as SUMO-1 can suppress AP2 and AP2-mediated transcription (8).
visualized by immunogold analysis of the nuclear envelope (32). Direct evidence for repression of transcriptional activity by sumoy-
Ubc9 interacts with Nup358 as well as RanGAP1/SUMO-1, and a lation is that fusion of SUMO to GAL4 drastically reduces its
model has been proposed in which these three proteins interact to activity in reporter gene assays (42). Furthermore, SUMO is also
Minireview: Regulation and Function of SUMO Modification 53901
able to inhibit transcription in trans as demonstrated by SUMO- does not appear to be mediated via sumoylation-induced changes in
dependent trans-repression of the VP-16 activation domain (43). topoisomerase II activity, because a dominant negative mutation in
The effects of SUMO on transcriptional activity may be compli- the Ubc9 (SUMO E2 conjugation enzyme) prevented sister chro-
cated by the finding that a number of transcription co-factors, such matid cohesion at the metaphase to anaphase transition but did
as GRIP1, SRC-1, and histone deacetylases (HDAC) 1 and 4, are not alter topoisomerase II activity (54). Sumoylation of other pro-
also sumoylated (1, 3, 6, 8). Sumoylation might be involved in teins such as the Psds5 protein has also been implicated in sister
modulating the functions of proteins as co-activators (GRIP1, chromatid cohesion. In the case of Psds5, which is a non-essential
SRC-1) or co-repressors (HDAC1, HDAC4) but is not essential (8). regulator of cohesion maintenance in yeast, results suggest that
Several observations reveal that the PIAS/SUMO system may mod- the desumoylation of this protein promotes sister chromatid disso-
ulate the assembly of coactivator or corepressor complexes that lution by rendering the cohesin complex, which acts as the molec-
regulate transcription (40). Other findings indicate further links ular glue between sister chromatids, accessible to other factors that
between the SUMO system and class I and class II HDACs that promote dissolution (55).
mediate transcription repression. For example, sumoylation of The role of SUMO-1 in mitotic chromosome structure is not
p300 can mediate repression of gene activity by recruitment of the limited to the cohesive properties of centromeres, as sumoylation
corepressor HDAC6 (44). The AR, which interacts with the core- has also been implicated in the maintenance and recruitment of
pressor SMRT, is part of a larger HDAC1-containing complex (45). proteins to the kinetochore, the protein complex that forms at the
Mutation of the sumoylation site in AR abrogates SMRT binding, centromere and recruits microtubules for anaphase separation. In

Downloaded from at LIFE SCIENCE LIBRARY, ACADEMIA SINICA on August 28, 2006
suggesting that sumoylation is required for the association of Saccharomyces cerevisiae, SUMO-1 has been shown to be a sup-
SMRT and class 1 HDACs. Similar data show that histone H4 pressor of a temperature-sensitive MIF2 (yeast homologue of
sumoylation mediates transcriptional repression through recruit- CENP-C), a protein which links ␣-satellite-containing centromeric
ment of HDAC1 and HP1 (46). However, sumoylation of methyl- DNA to the proteins of the inner kinetochore plate (56). Interest-
transferase 3a (Dnmt3a) disrupts its ability to interact with ingly, neither CENP-C nor MIF2 is sumoylated, and thus the role
HDAC1/2, which abolishes its capacity to repress transcription of sumoylation is thought to be indirect (57). In addition to modi-
(47). Regarding other possible mechanisms by which sumoylation fying several central kinetochore/centromere proteins, sumoylation
could mediate effects on transcription factors/co-factors, examples is also thought to target various proteins to this region during
where sumoylation has been found to regulate ubiquitination of mitosis for reasons which remain unclear. For example, during
proteins such as NF␬B inhibitor I␬B␣, PCNA, Smad4, and Mdm2, mitosis SUMO-1 targets RanGAP1 to the mitotic spindles and
either directly by competition for the modified lysine or indirectly, kinetochores, and at the kinetochores specifically, RanBP2/Nup358
leaves open the possibility that some effects of sumoylation could colocalizes specifically at the kinetochore (58).
be mediated via control of protein levels in general or turnover of In addition to the apparent role of sumoylation in chromosome
specific subpopulations of a protein in a cell (3, 6, 48). maintenance and kinetochore assembly/disassembly, the sumoyla-
Although sumoylation of most transcription factors results in tion modification of a number of critical tumor suppressor and
repression, SUMO modification appears to have positive effects on repair proteins implicated SUMO-1 as an integral player in main-
transcriptional activation by the heat shock factors HSF1 and taining genomic stability. p53 and Mdm2 are both targets of
HSF2 and the ␤-catenin-activated factor Tcf-4. Sumoylation of sumoylation, which has functional effects on the activities of these
HSF1 and HSF2, which is stress-induced in the case of HSF1 but proteins (3, 6, 7, 48). Evidence indicates that components of the
can be observed for HSF2 present in non-stressed cells, is corre- Wnt signaling cascade (e.g. axin, ␤-catenin, LEF/Tcf-4) are also
lated with their localization to PML NBs (31, 49). For both HSFs, targets of sumoylation, which may regulate the system at multiple
in vitro sumoylation leads to increased DNA-binding activity, but vertical and horizontal steps (3, 6, 7). Although sumoylation ap-
in the case of HSF1, mutation of the sumoylation site did not parently affects cell cycle and developmental proteins, the integrity
appear to block stress-induced DNA-binding activity in cells (21, of DNA itself may also rely on the sumoylation status of various
31, 49). One possibility is that, because of the critical importance of proteins, particularly those involved in DNA repair. Both UBL1
inducing heat shock protein expression in response to cellular stress, (SUMO-1) and UBE2I (Ubc9) have been identified to interact with
cells may have evolved multiple independent pathways for activating RAD51/52, proteins well known for their role in homologous recom-
HSF1 DNA binding, of which sumoylation is only one. Tcf-4-depend- bination and repairing double-stranded breaks in cells (59, 60).
ent transcription is activated by coexpression of ␤-catenin and PIASy, Sumoylation has also been implicated in the repair of the DNA
and this activation is reduced when Tcf-4 lacks SUMO attachment damage mediated by topoisomerase II (61, 62), which is of clinical
sites, suggesting that sumoylation activates Tcf-4 (50). A protein relevance because topoisomerase is a target of numerous anti-cancer
called DJ-1, originally identified as a Myc-interacting protein, posi- therapies. More recent evidence suggests that the Rad6 postreplica-
tively regulates AR activity and also appears to be modified by tive repair pathway is apparently sumoylation-dependent, particu-
SUMO, and mutation of the acceptor lysine destroys the capacity of larly with respect to PCNA, the activity of which varies by which
DJ-1 to positively regulate AR activity (13). molecular tag (e.g. SUMO-1 or ubiquitin) it carries (63, 64). The
balance between sumoylation and ubiquitination of PCNA, which
Role of SUMO in Genomic Integrity and Chromosomes determines which specific repair pathway the cell utilizes, illustrates
Since its discovery, sumoylation has held an important role in the critical role of sumoylation in this important cell function.
cell biology that extends into fields such as chromosome cohesion
and kinetochore assembly. During mitosis, the proper distribution SUMO and Viral Proteins
of chromosomes into replicated cells is a highly ordered and com- Two major-immediate-early (MIE) proteins critical for propaga-
plex process that is dependent upon the proper timing of sister tion of the human cytomegalovirus and herpesvirus, IE1 (IE1-p72
chromatid assembly and separation. Misregulation of this process or IE72) and IE2 (IE2-p86 or IE86), have been found to be sumo-
was one of the first phenotypes described in SUMO-1 (Smt3/Pmt3) ylated. In the case of the IE1 protein, which is known to interact
mutants in yeast, characterized by aberrant mitosis and defects in with PML, blocking this modification does not disrupt targeting of
chromosomal segregation (51, 52). Other components of the sumoy- this protein to ND10 nuclear bodies nor does it affect ND10 orga-
lation machinery, such as the E2 conjugating enzyme and SUMO nization, suggesting that sumoylation is not a prerequisite for the
isopeptidases, have also been shown to be important for this proc- derepressive activities of IE1 (65, 66). However, IE1 does modulate
ess. For example, the SUMO-1 isopeptidase in budding yeast the sumoylation of PML and is important for effects on nuclear
(Smt4) acts as a key regulator of centromeric chromatid cohesion body dynamics (67). Targeting of IE2 to ND10 is not affected by
(53). The same study also suggested that the yeast homologue of mutations of its target lysine residues, but sumoylation appears to
topoisomerase II (Top2) was the SUMO-1 substrate important for be critical for IE2-mediated transactivation (68). Recent studies
this process, because topoisomerase II mutants lacking SUMO-1 have also shown that PIAS1 can increase the levels of IE2 sumoyl-
modifications sites can rescue defects in the isopeptidase mutants ation which leads to enhanced IE2-mediated transactivation (69).
(53). In support of this idea, topoisomerase II was found to be the The BZLF1 (Z) protein of Epstein-Barr virus (EBV) is SUMO-1-
major high molecular weight, chromatin-dependent sumoylated modified at lysine 12 within the transactivation domain, and re-
protein in mitotic Xenopus extracts (54). Interestingly, this effect sults suggest that BZLF1 sumoylation decreases PML SUMO mod-
53902 Minireview: Regulation and Function of SUMO Modification
ification by competing for limiting amounts of free SUMO protein 28. Sternsdorf, T., Jensen, K., Reich, B., and Will, H. (1999) J. Biol. Chem. 274,
(70). The immediate early protein E1 of bovine papillomavirus was 12555–12566
29. Weger, S., Hammer, E., and Engstler, M. (2003) Exp. Cell Res. 290, 13–27
found to interact both in vivo and in vitro with Ubc9 using a yeast 30. Chakrabarti, S. R., Sood, R., Nandi, S., and Nucifora, G. (2000) Proc. Natl.
two-hybrid screen and to be sumoylated at lysine residue 514 (71). Acad. Sci. U. S. A. 97, 13281–13285
Mutations within E1 that prevent SUMO-1 modification do not 31. Hong, Y., Rogers, R., Matunis, M. J., Mayhew, C. N., Goodson, M. L., Park-
affect intracellular stability but do disrupt nuclear import and Sarge, O. K., and Sarge, K. D. (2001) J. Biol. Chem. 276, 40263– 40267
32. Zhang, H., Saitoh, H., and Matunis, M. J. (2002) Mol. Cell. Biol. 22, 6498 – 6508
accumulation leading to the decreased ability of E1 to replicate the 33. Pichler, A., and Melchior, F. (2002) Traffic 3, 381–387
viral genome (71, 72). 34. Hang, J., and Dasso, M. (2002) J. Biol. Chem. 277, 19961–19966
A number of adenoviral proteins important for viral replication 35. Li, S. J., and Hochstrasser, M. (2003) J. Cell Biol. 160, 1069 –1081
36. Stade, K., Vogel, F., Schwienhorst, I., Meusser, B., Volkwein, C., Nentwig, B.,
have also been shown to be sumoylated. Adenoviral E1B is modi-
Dohmen, R. J., and Sommer, T. (2002) J. Biol. Chem. 277, 49554 – 49561
fied at SUMO-1 at lysine 104, which is important for the ability of 37. Sobko, A., Ma, H., and Firtel, R. A. (2002) Dev. Cell 2, 745–756
this protein to transform primary cells and inhibit p53-mediated 38. Wood, L. D., Irvin, B. J., Nucifora, G., Luce, K. S., and Hiebert, S. W. (2003)
transactivation, and also appears to mediate E1B localization to Proc. Natl. Acad. Sci. U. S. A. 100, 3257–3262
39. Vassileva, M. T., and Matunis, M. J. (2004) Mol. Cell. Biol. 24, 3623–3632
the nucleus (73). Expression of adenoviral Gam1 leads to a global 40. Schmidt, D., and Muller, S. (2003) Cell Mol. Life Sci. 60, 2561–2574
reduction in sumoylation including the reduced sumoylation of 41. Ohshima, T., Koga, H., and Shimotohno, K. (2004) J. Biol. Chem. 279,
HDAC1, dispersal of PML-containing nuclear bodies, and delocaliza- 29551–29557
tion of SUMO-1 (74). The adenovirus E1A protein has been shown to 42. Ross, S., Best, J. L., Zon, L. I., and Gill, G. (2002) Mol. Cell 10, 831– 842

Downloaded from at LIFE SCIENCE LIBRARY, ACADEMIA SINICA on August 28, 2006
43. Yang, S. H., Jaffray, E., Hay, R. T., and Sharrocks, A. D. (2003) Mol. Cell 12,
physically interact with the SUMO E2 Ubc9 protein although no 63–74
clear role has been identified (75). In addition, yeast two-hybrid 44. Girdwood, D., Bumpass, D., Vaughan, O. A., Thain, A., Anderson, L. A.,
analysis indicated that the geminivirus TYLCSV protein Rep inter- Snowden, A. W., Garcia-Wilson, E., Perkins, N. D., and Hay, R. T. (2003)
acts with a Ubc9 homologue from Nicotiana benthamiana (NbSCE1), Mol. Cell 11, 1043–1054
45. Dotzlaw, H., Moehren, U., Mink, S., Cato, A. C., Iniguez Lluhi, J. A., and
but it is not clear if Rep is a substrate for sumoylation (76). Baniahmad, A. (2002) Mol. Endocrinol. 16, 661– 673
46. Shiio, Y., and Eisenman, R. N. (2003) Proc. Natl. Acad. Sci. U. S. A. 100,
Perspectives 13225–13230
Investigation of the regulation and function of SUMO modifica- 47. Ling, Y., Sankpal, U. T., Robertson, A. K., McNally, J. G., Karpova, T., and
tion of proteins is an exciting and rapidly growing field. The recent Robertson, K. D. (2004) Nucleic Acids Res. 32, 598 – 610
48. Melchior, F., and Hengst, L. (2002) Cell Cycle 1, 245–249
use of broad proteomics approaches to identify large numbers of 49. Goodson, M. L., Hong, Y., Rogers, R., Matunis, M. J., Park-Sarge, O. K., and
new putative sumoylated proteins will only add to the already Sarge, K. D. (2001) J. Biol. Chem. 276, 18513–18518
rapid pace of advance (77– 81). Key areas requiring further inves- 50. Yamamoto, H., Ihara, M., Matsuura, Y., and Kikuchi, A. (2003) EMBO J. 22,
tigation include understanding the underlying molecular and bio- 2047–2059
51. Tanaka, K., Nishide, J., Okazaki, K., Kato, H., Niwa, O., Nakagawa, T.,
chemical mechanisms by which this modification plays its critical Matsuda, H., Kawamukai, M., and Murakami, Y. (1999) Mol. Cell. Biol. 19,
roles in regulating subcellular localization, transcription, chromo- 8660 – 8672
some function, and genomic integrity, to name a few, and to un- 52. Biggins, S., Bhalla, N., Chang, A., Smith, D. L., and Murray, A. W. (2001)
derstand how sumoylation leads to different effects in different Genetics 159, 453– 470
53. Bachant, J., Alcasabas, A., Blat, Y., Kleckner, N., and Elledge, S. J. (2002) Mol.
proteins. Further investigation of the mechanisms and function of Cell 9, 1169 –1182
nuclear pore-associated sumoylation, including identification of ad- 54. Azuma, Y., Arnaoutov, A., and Dasso, M. (2003) J. Cell Biol. 163, 477– 487
ditional proteins that are sumoylated at this cellular site, should 55. Stead, K., Aguilar, C., Hartman, T., Drexel, M., Meluh, P., and Guacci, V.
also yield interesting new results and better understanding of the (2003) J. Cell Biol. 163, 729 –741
56. Meluh, P. B., and Koshland, D. (1995) Mol. Biol. Cell 6, 793– 807
role of this important protein modification. 57. Fukagawa, T., Regnier, V., and Ikemura, T. (2001) Nucleic Acids Res. 29,
3796 –3803
REFERENCES 58. Joseph, J., Tan, S. H., Karpova, T. S., McNally, J. G., and Dasso, M. (2002)
1. Seeler, J. S., and Dejean, A. (2001) Oncogene 20, 7243–7249 J. Cell Biol. 156, 595– 602
2. Melchior, F., Schergaut, M., and Pichler, A. (2003) Trends Biochem. Sci. 28, 59. Shen, Z., Pardington-Purtymun, P. E., Comeaux, J. C., Moyzis, R. K., and
612– 618 Chen, D. J. (1996) Genomics 37, 183–186
3. Johnson, E. S. (2004) Annu. Rev. Biochem. 73, 355–382 60. Shen, Z., Pardington-Purtymun, P. E., Comeaux, J. C., Moyzis, R. K., and
4. Schwartz, D. C., and Hochstrasser, M. (2003) Trends Biochem. Sci. 28, Chen, D. J. (1996) Genomics 36, 271–279
321–328 61. Mo, Y. Y., Yu, Y., Shen, Z., and Beck, W. T. (2002) J. Biol. Chem. 277,
5. Hay, R. T., Vuillard, L., Desterro, J. M., and Rodriguez, M. S. (1999) Philos. 2958 –2964
Trans. R. Soc. Lond. B Biol. Sci. 354, 1601–1609 62. Mao, Y., Sun, M., Desai, S. D., and Liu, L. F. (2000) Proc. Natl. Acad. Sci.
6. Muller, S., Ledl, A., and Schmidt, D. (2004) Oncogene 23, 1998 –2008 U. S. A. 97, 4046 – 4051
7. Seeler, J. S., and Dejean, A. (2003) Nat. Rev. Mol. Cell. Biol. 4, 690 – 699 63. Hoege, C., Pfander, B., Moldovan, G. L., Pyrowolakis, G., and Jentsch, S.
8. Verger, A., Perdomo, J., and Crossley, M. (2003) EMBO Rep. 4, 137–142 (2002) Nature 419, 135–141
9. Bohren, K. M., Nadkarni, V., Song, J. H., Gabbay, K. H., and Owerbach, D. 64. Stelter, P., and Ulrich, H. D. (2003) Nature 425, 188 –191
(2004) J. Biol. Chem. 279, 27233–27238 65. Xu, Y., Ahn, J. H., Cheng, M., apRhys, C. M., Chiou, C. J., Zong, J., Matunis,
10. Pickart, C. M. (2001) Annu. Rev. Biochem. 70, 503–533 M. J., and Hayward, G. S. (2001) J. Virol. 75, 10683–10695
11. Johnson, E. S., and Gupta, A. A. (2001) Cell 106, 735–744 66. Gravel, A., Dion, V., Cloutier, N., Gosselin, J., and Flamand, L. (2004) J. Gen.
12. Sachdev, S., Bruhn, L., Sieber, H., Pichler, A., Melchior, F., and Grosschedl, R. Virol. 85, 1319 –1328
(2001) Genes Dev. 15, 3088 –3103 67. Lee, H. R., Kim, D. J., Lee, J. M., Choi, C. Y., Ahn, B. Y., Hayward, G. S., and
13. Takahashi, K., Taira, T., Niki, T., Seino, C., Iguchi-Ariga, S. M., and Ariga, H. Ahn, J. H. (2004) J. Virol. 78, 6527– 6542
(2001) J. Biol. Chem. 276, 37556 –37563 68. Hofmann, H., Floss, S., and Stamminger, T. (2000) J. Virol. 74, 2510 –2524
14. Kotaja, N., Karvonen, U., Janne, O. A., and Palvimo, J. J. (2002) Mol. Cell. 69. Lee, J. M., Kang, H. J., Lee, H. R., Choi, C. Y., Jang, W. J., and Ahn, J. H.
Biol. 22, 5222–5234 (2003) FEBS Lett. 555, 322–328
15. Pichler, A., Gast, A., Seeler, J. S., Dejean, A., and Melchior, F. (2002) Cell 108, 70. Adamson, A. L., and Kenney, S. (2001) J. Virol. 75, 2388 –2399
109 –120 71. Rangasamy, D., and Wilson, V. G. (2000) J. Biol. Chem. 275, 30487–30495
16. Kagey, M. H., Melhuish, T. A., and Wotton, D. (2003) Cell 113, 127–137 72. Rangasamy, D., Woytek, K., Khan, S. A., and Wilson, V. G. (2000) J. Biol.
17. Takahashi, Y., Toh-e, A., and Kikuchi, Y. (2001) Gene (Amst.) 275, 223–231 Chem. 275, 37999 –38004
18. Hershko, A., and Ciechanover, A. (1998) Annu. Rev. Biochem. 67, 425– 479 73. Endter, C., Kzhyshkowska, J., Stauber, R., and Dobner, T. (2001) Proc. Natl.
19. Tatham, M. H., Jaffray, E., Vaughan, O. A., Desterro, J. M., Botting, C. H., Acad. Sci. U. S. A. 98, 11312–11317
Naismith, J. H., and Hay, R. T. (2001) J. Biol. Chem. 276, 35368 –35374 74. Colombo, R., Boggio, R., Seiser, C., Draetta, G. F., and Chiocca, S. (2002)
20. Hilgarth, R. S., Hong, Y., Park-Sarge, O. K., and Sarge, K. D. (2003) Biochem. EMBO Rep. 3, 1062–1068
Biophys. Res. Commun. 303, 196 –200 75. Hateboer, G., Hijmans, E. M., Nooij, J. B., Schlenker, S., Jentsch, S., and
21. Hietakangas, V., Ahlskog, J. K., Jakobsson, A. M., Hellesuo, M., Sahlberg, Bernards, R. (1996) J. Biol. Chem. 271, 25906 –25911
N. M., Holmberg, C. I., Mikhailov, A., Palvimo, J. J., Pirkkala, L., and 76. Castillo, A. G., Kong, L. J., Hanley-Bowdoin, L., and Bejarano, E. R. (2004)
Sistonen, L. (2003) Mol. Cell. Biol. 23, 2953–2968 J. Virol. 78, 2758 –2769
22. Matunis, M. J., Coutavas, E., and Blobel, G. (1996) J. Cell Biol. 135, 77. Zhao, Y., Kwon, S. W., Anselmo, A., Kaur, K., and White, M. A. (2004) J. Biol.
1457–1470 Chem. 279, 20999 –21002
23. Mahajan, R., Gerace, L., and Melchior, F. (1998) J. Cell Biol. 140, 259 –270 78. Vertegaal, A. C., Ogg, S. C., Jaffray, E., Rodriguez, M. S., Hay, R. T., Andersen,
24. Mahajan, R., Delphin, C., Guan, T., Gerace, L., and Melchior, F. (1997) Cell 88, J. S., Mann, M., and Lamond, A. I. (2004) J. Biol. Chem. 279, 33791–33798
97–107 79. Zhou, W., Ryan, J. J., and Zhou, H. (2004) J. Biol. Chem. 279, 32262–32268
25. Matunis, M. J., Wu, J., and Blobel, G. (1998) J. Cell Biol. 140, 499 –509 80. Panse, V. G., Hardeland, U., Werner, T., Kuster, B., and Hurt, E. (2004)
26. Lin, X., Liang, M., Liang, Y. Y., Brunicardi, F. C., and Feng, X. H. (2003) J. Biol. Chem. 279, 41346 – 41351
J. Biol. Chem. 278, 31043–31048 81. Wohlschlegel, J. A., Johnson, E. S., Reed, S. I., and Yates, J. R., III (2004)
27. Sternsdorf, T., Jensen, K., and Will, H. (1997) J. Cell Biol. 139, 1621–1634 J. Biol. Chem. 279, 45662– 45668