# SUMO: regulating the regulator

G. Bossis, F. Melchior

► To cite this version:

G. Bossis, F. Melchior. SUMO: regulating the regulator. Cell Division, 2006, 1, pp.13. 10.1186/1747-1028-1-13. hal-02262455

HAL Id: hal-02262455

https://hal.science/hal-02262455

Submitted on 2 Jun 2021

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Review

Open Access

# SUMO: regulating the regulator

Guillaume Bossis¹,² and Frauke Melchior*²

Address: ¹Institut de Génétique Moléculaire de Montpellier, CNRS, 1919 route de Mende, 34293 - Montpellier Cedex 05, France and ²Dept. of Biochemie I, University Goettingen, Humboldt Allee 23, 37073 Goettingen, Germany

Email: Guillaume Bossis - guillaume.bossis@igmm.cnrs.fr; Frauke Melchior* - F.Melchior@medizin.uni-goettingen.de

Published: 29 June 2006

Received: 14 June 2006

Cell Division 2006, 1:13 doi:10.1186/1747-1028-1-13

Accepted: 29 June 2006

This article is available from: http://www.celldiv.com/content/1/1/13

© 2006 Bossis and Melchior; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## 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.

## The many roles of sumoylation

Sumoylation, which consists in the covalent and reversible conjugation of Small Ubiquitin-related Modifiers (SUMO-1, 2 and 3 in mammals) to target proteins, is an essential cellular process from yeasts to mammals. In S. cerevisiae, disruption of the SUMO pathway leads to a G2/M cell cycle arrest [1]; In mouse, it leads to embryonic death at early stages [2].

The number of known SUMO targets is growing exponentially, and it seems likely that this modification is as common as phosphorylation to regulate biological processes [3]. Most SUMO targets were initially found in the nucleus, but it is now clear that sumoylation also regulates cytoplasmic-, and even plasma membrane associated proteins. Modification has been linked to pathways as diverse as intracellular trafficking, cell cycle, DNA repair and replication, RNA metabolism and cell signalling (for detailed description of sumoylation functions see [4]). At a molecular level, sumoylation alters protein functions by masking and/or adding interaction surfaces, or by inducing conformational changes that result in altered interactions

(for detailed examples see [5]). As a consequence, a wide variety of downstream consequences have been observed, including changes in localisation, enzymatic activity, or stability.

Among the many known targets of sumoylation, a large number are regulators of gene expression, in particular transcription factors, co-activators or repressors. Here, the emerging picture is that sumoylation essentially results in down-regulation of gene expression. Albeit the molecular mechanisms underlying this repression by SUMO are still ill defined, they seem to involve SUMO-dependent recruitment of transcriptional repressors such as HDACs directly to promoters [6].

## The SUMO conjugation and deconjugation pathway

All SUMO isoforms are conjugated via a conserved enzymatic cascade that resembles that of ubiquitin conjugation (Figure 1). SUMO is first activated by formation of a thioester bond between its C-terminal glycine and the catalytic cysteine of the heterodimeric E1 activating enzyme

<footnote>* Corresponding author</footnote>
<figure><img src="image_2.png" /><figcaption>**Figure 1**</figcaption></figure>

**The SUMO pathway.** All SUMO isoforms are synthetized as a precursor, containing a C-terminal extension, which is cleaved by specific hydrolases. Mature SUMO is then activated by formation of a thioester bond between its C-terminal glycine and the catalytic cysteine of the Uba2 subunit from the E1 activating enzyme (Aos1/Uba2). This step requires ATP hydrolysis. SUMO is then tranfered to the catalytic cysteine of the E2 activating enzyme Ubc9. The last step of the conjugating cascade consists in the transfer of SUMO from Ubc9 to the ε-NH2 group of a lysine side chain (isopeptide bond formation). Efficient modification usually requires E3 ligases. SUMOylation is a reversible and highly dynamic modification due to the presence of specific cysteine proteases of the Ulp/Senp family that cleave the isopeptide bond.

(Aos1/Uba2, also named SAE1/SAE2). This step requires ATP hydrolysis. SUMO is then transferred to the catalytic cysteine of the single E2 conjugating enzyme Ubc9. The last step consists in the transfer of SUMO from the E2 to the ε-amino group of a lysine side chain on the substrate, which results in isopeptide bond formation. For this, Ubc9 needs to recognize a specific acceptor site in the target. Many – but not all – targets contain the so-called SUMO consensus motif, ψKxE, where ψ is a large hydrophobic residue and K the acceptor lysine. The interaction between Ubc9 and most targets is not stable enough for efficient transfer, and therefore requires additional pro-

teins, the so-called E3 ligases. Currently known ligases include PIAS (Protein inhibitor of activated STAT) proteins, the nucleoporin RanBP2/Nup358 and the polycomb protein Pc2 [7,5,4].

SUMO-target conjugates are susceptible to cleavage by specific cysteine proteases (SUMO isopeptidases) [7]. In yeast, two isopeptidases, Ulp1 and Ulp2, are responsible for SUMO deconjugation. Homologs of the Ulp family were identified by sequence homology and referred to as SENP proteins (1 to 8). SUMO isopeptidase activity was confirmed for SENP-1 [8], SENP-2 [9-11], SENP-3
## Competition with other lysinemodifiers

<figure><img src="image_3.png" /></figure>

## Regulation by phosphorylation

<figure><img src="image_4.png" /><figcaption>**Figure 2**</figcaption></figure>

**Regulation of SUMOylation through target modification.** Distinct post-translational modifications of the target protein can affect its sumoylation. A) Competition with other lysine-directed modifications such as ubiquitinylation of acetylation abolishes sumoylation. B) Phosphorylation can act both as a positive and a negative regulator of sumoylation. Enhanced sumoylation has been observed, e.g., when the phosphorylated residue is part of an extended SUMO acceptor site, the PDSM (Phosphorylation Dependant SUMO Motif; with the sequence motif ΨKxExxSP [30]).

[12,13], SENP5 [13] and SENP6 [14]. SENP-8, however, turned out to be a NEDD8 specific isopeptidase [15-17]. Whether other types of SUMO isopeptidases exist is still not clear. All SENPs share a conserved catalytic domain but have distinct N-terminal extensions, which might be responsible for their different intracellular localisations [7].

The interplay between modifying enzymes and isopeptidases is responsible, at least in part, for the late discovery of SUMO: with rare exceptions such as RanGAP1, the first protein for which sumoylation was shown, most SUMO

targets are modified at very low steady state levels in vivo. Moreover, upon cell lysis most sumoylated proteins are highly susceptible to demodification by isopeptidases. Dynamic sumoylation/desumoylation cycles may also be responsible for a frequently observed conundrum: while only a small fraction of a given target is sumoylated at steady state, their corresponding SUMOylation-deficient mutants can have striking effects [4].

### Regulation of sumoylation at the substrate level

While selected SUMO targets are modified constitutively, many proteins are sumoylated in a temporally or spatially
regulated fashion. Examples for target specific regulation are mitotic modification of yeast septins [18] and topoisomerase II [19], PML demodification [20] in mitosis, S. c. PCNA sumoylation in S-phase [21,22], stress induced sumoylation of heat shock factor I [23], or circadian cycle dependant sumoylation of BMAL1 [24]. While only fragmented knowledge concerning this regulation is available, it is already clear that there are several distinct mechanisms to enhance or inhibit sumoylation of individual target proteins.

One obvious way to regulate sumoylation at the target level is through target phosphorylation (Figure 2). As will become evident from the examples below, phosphorylation may serve both as a positive and a negative signal for sumoylation. An example for negative regulation is the sumoylation of AP-1 transcription factors c-Jun and c-Fos, which is reduced after phosphorylation of specific residues (Ser 63 and 73 for c-Jun and Thr 232 for c-Fos) by JNK (in the case of c-Jun) and by an unidentified, Ras activated, kinase in the case of c-Fos [25,26]. Consistent with the finding that sumoylation inhibits their transcriptional activity, phosphorylation of these residues is known to activate c-Jun and c-Fos dependent transcription. Along the same line, phosphorylation of p53 at Ser 20, induced by DNA damaging agents, strongly reduces its sumoylation [27]. ELK-1 phosphorylation upon activation of the MAPK pathway was also shown to inhibit its sumoylation [28]. Whether phosphorylation serves to recruit isopeptidases, blocks access of Ubc9 or E3 ligases, or prevents modification by other mechanisms is currently unknown.

In other cases, phosphorylation can enhance sumoylation. This was first demonstrated for the Heat Shock Factor HSF1. Its phosphorylation on Ser 303, induced after heat shock, is required for efficient sumoylation on the nearby Lys 298 [29]. A S303E mutant is more efficiently sumoylated than wt even in vitro, suggesting that the underlying mechanism is enhanced recruitment of the E2 conjugating enzyme Ubc9 E3 (ligases were absent in the assay). Whether this involves a conformational change or whether the acidic residue contributes directly to Ubc9 association awaits further analysis. Importantly, these findings could be generalized: The sequence motif, ΨKxExxSP, which is now referred to as Phosphorylation Dependent Sumoylation Motif (PDSM) [30], is present in various proteins, predominantly transcriptional regulators. For several of these (HSF4, GATA-1, MEF2, SNIP-1 and ERRγ) the authors demonstrated that serine phosphorylation in the PDSM indeed enhances their sumoylation [30]. Phosphorylation dependent sumoylation of MEF2 family members was also reported by other groups [31,32].

Regulated MEF2 sumoylation seems to actually involve an added level of complexity: Zhao and coworkers [33] had already observed that MEF2D can be sumoylated or acetylated on the same lysine residue. A report by Shalizi et al., [34] now brings together phosphorylation, acetylation and sumoylation of MEF2A: Calcineurin dependent dephosphorylation of Ser 408 in MEF2A, which is located in the PDSM, was shown to promote a switch from sumoylation to acetylation at lysine 403. Consequently, sumoylation of MEF2 is inhibited not only by the lack of the phosphate in the PDSM, but also by direct competition of acetylation and sumoylation on the same lysine residue.

The concept that sumoylation and acetylation are two competing modifications for the same lysine residue in some SUMO targets is actually not new – it has been first noted for the transcription factor Sp3 [35], and was also shown for the transcriptional co-activator p300, whose deacetylation by SIRT1 is required for its efficient sumoylation [36]. Whether sumoylation serves to inhibit acetylation, whether acetylation serves to prevent sumoylation, or whether the sumoylated, acetylated and non-modified species serve independent functions is one of many interesting questions that arise from these studies. One particularly interesting question is whether lysine acetylation frequently overlaps with SUMO acceptor sites.

Lysine residues are obviously not only targets for sumoylation and acetylation, but can, e.g., also be ubiquitinated. This brings us to another type of competing modifications – ubiquitinylation and sumoylation (Figure 2). The first example is Iκ-Bα that can be poly-ubiquitinated or mono-sumoylated on lysine 21 [37]. While poly-ubiquitinylation and subsequent degradation by the proteasome requires signal-induced phosphorylation of Iκ-Bα, sumoylation takes place in the absence of phosphorylation. It has been suggested that SUMO serves to protect Iκ-Bα from degradation, however only a very small fraction of Iκ-Bα is sumoylated at steady state. More recently, it has been shown that NEMO, the Iκ-B kinase (IKK) regulator, is also subject to both modifications on the same lysine [38]. Here, sumoylation/desumoylation and ubiquitinylation may be independent, but consecutive, events in the activation pathway [39]. Finally, S.c. and Xenopus laevis PCNA were shown to be mono-ubiquitinated, poly-ubiquitinated (K63 chains) or sumoylated on lysine 164. Different modifications are induced by different cues (e.g., cell cycle position or DNA damage), and have distinct as well as cooperative functions in DNA repair and replication (reviewed in [40]). In conclusion, quantitative and stable modification of a given target with SUMO or ubiquitin would obviously prevent modification with the other moiety, and either modifier could hence serve as an antagonist of the other. However, from
## Inhibition of SUMO conjugation by Gam1 viral protein

<figure><img src="image_5.png" /></figure>

## Inhibition of SUMO conjugation by Reactive Oxygen Species

<figure><img src="image_6.png" /></figure>

**Figure 3**
**Global regulation of the conjugating machinery.** A) The Gam1 protein from CELO adenovirus reduces E1 and E2 enzyme levels [47]. The resulting global desumoylation correlates with increased transcriptional activity, which is due, at least in part, to desumoylation of transcription factors such as Sp3. B) $H_2O_2$ inhibits SUMO conjugation by inducing the formation of a disulfide bond between the catalytic cysteines of the E1 and E2 enzymes. Depending on the source and dose of $H_2O_2$ (applied exogenously or produced endogenously) this results in local desumoylation of specific proteins or global desumoylation [52].

the currently known data it seems more likely that both types of modifications are regulated independent of each other and serve different roles (reviewed in [41]).

The mechanisms discussed above all involve posttranslational modifications of the target protein. Similar mechanisms can obviously be envisioned at the level of target
Highest levels of endogenous H₂O₂ production are known to occur in phagocytic cells. Their activation by endotoxins (such as LPS) or inflammatory mediators (such as TNF, Interferon or Phorbol esters) is responsible for the so-called respiratory burst, which consists in the production of ROS by a specific NADPH oxidase complex called Phox [54]. While it was long thought that this ROS production was only aimed at killing the engulfed pathogen, it is now known that these ROS also play a key role as second messengers in AP-1 and NF-κB signaling pathways [56]. At least in this system, or more precisely in a macrophage cell line activated by PMA and zymosan, endogenously produced H₂O₂ is sufficient to reversibly inactivate a significant fraction of cytoplasmic SUMO E1 and E2 enzymes. While the global pattern of SUMO conjugates remains unchanged, some demodification of unknown proteins has been observed [52]. One attractive hypothesis is that signal induced desumoylation of specific proteins in the immediate vicinity of NADPH oxidases, both in macrophages and other cell types, may contribute to activation of signal transduction and subsequent cellular responses.

## Conclusion

Considering the enormous number of sumoylated proteins that are modified in temporally and spatially controlled manner, the number of known enzymes is surprisingly limited. Nevertheless, in vitro, these enzymes are sufficient to modify many proteins. To account for the high specificity observed in vivo, we therefore have to assume the existence of many regulatory mechanisms. As outlined in this review, we are now beginning to understand how sumoylation can be regulated -mechanisms such as phosphorylation of selected targets and enzymes, antagonistic modifications and local inactivation by oxidation appear to contribute at the level of individual targets and in some scenarios globally. Different aspects of these and other regulatory mechanisms will undoubtedly be the focus of many exciting contributions over the next few years.

## References

1. Seufert W, Futcher B, Jentsch S: **Role of a ubiquitin-conjugating enzyme in degradation of S- and M-phase cyclins.** *Nature* 1995, **373**:78-81.

2. Nacerddine K, Lehembre F, Bhaumik M, Artus J, Cohen-Tannoudji M, Babinet C, Pandolfi PP, Dejean A: **The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice.** *Dev Cell* 2005, **9**:769-779.

3. Marx J: **Cell biology. SUMO wrestles its way to prominence in the cell.** *Science* 2005, **307**:836-839.

4. Hay RT: **SUMO: a history of modification.** *Mol Cell* 2005, **18**:1-12.

5. Johnson ES: **Protein modification by SUMO.** *Annu Rev Biochem* 2004, **73**:355-382.

6. Gill G: **Something about SUMO inhibits transcription.** *Curr Opin Genet Dev* 2005, **15**:536-541.

7. Melchior F, Schergaut M, Pichler A: **SUMO: ligases, isopeptidases and nuclear pores.** *Trends Biochem Sci* 2003, **28**:612-618.

8. Bailey D, O'Hare P: **Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1.** *J Biol Chem* 2004, **279**:692-703.

9. Best JL, Ganiatsas S, Agarwal S, Changou A, Salomoni P, Shirihai O, Meluh PB, Pandolfi PP, Zon LI: **SUMO-1 protease-1 regulates gene transcription through PML.** *Mol Cell* 2002, **10**:843-855.

10. Kadoya T, Yamamoto H, Suzuki T, Yukita A, Fukui A, Michiue T, Asahara T, Tanaka K, Asashima M, Kikuchi A: **Desumoylation activity of Axam, a novel Axin-binding protein, is involved in down-regulation of beta-catenin.** *Mol Cell Biol* 2002, **22**:3803-3819.

11. Nishida T, Kaneko F, Kitagawa M, Yasuda H: **Characterization of a novel mammalian SUMO-1/Smt3-specific isopeptidase, a homologue of rat axam, which is an axin-binding protein promoting beta-catenin degradation.** *J Biol Chem* 2001, **276**:39060-39066.

12. Nishida T, Tanaka H, Yasuda H: **A novel mammalian Smt3-specific isopeptidase 1 (SMT3IP1) localized in the nucleolus at interphase.** *Eur J Biochem* 2000, **267**:6423-6427.

13. Gong L, Yeh ET: **Characterization of a family of nucleolar sumo-specific proteases with preference for sumo-2 or sumo-3.** *J Biol Chem* 2006.

14. Kim KI, Baek SH, Jeon YJ, Nishimori S, Suzuki T, Uchida S, Shimbara N, Saitoh H, Tanaka K, Chung CH: **A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs.** *J Biol Chem* 2000, **275**:14102-14106.

15. Gan-Erdene T, Nagamalleswari K, Yin L, Wu K, Pan ZQ, Wilkinson KD: **Identification and characterization of DEN1, a ded nedylase of the ULP family.** *J Biol Chem* 2003, **278**:28892-28900.

16. Mendoza HM, Shen LN, Botting C, Lewis A, Chen J, Ink B, Hay RT: **NEDP1, a highly conserved cysteine protease that deNED-Dylates Cullins.** *J Biol Chem* 2003, **278**:25637-25643.

17. Wu K, Yamoah K, Dolios G, Gan-Erdene T, Tan P, Chen A, Lee CG, Wei N, Wilkinson KD, Wang R, Pan ZQ: **DEN1 is a dual function protease capable of processing the C terminus of Nedd8 and deconjugating hyper-neddylated CUL1.** *J Biol Chem* 2003, **278**:28882-28891.

18. Johnson ES, Blobel G: **Cell cycle-regulated attachment of the ubiquitin-related protein SUMO to the yeast septins.** *J Cell Biol* 1999, **147**:981-994.

19. Azuma Y, Arnaoutov A, Dasso M: **SUMO-2/3 regulates topoisomerase II in mitosis.** *J Cell Biol* 2003, **163**:477-487.

20. Everett RD, Lomonte P, Sternsdorf T, van Driel R, Orr A: **Cell cycle regulation of PML modification and ND10 composition.** *J Cell Sci* 1999, **112** (Pt 24):4581-4588.

21. Papouli E, Chen S, Davies AA, Huttner D, Krejci L, Sung P, Ulrich HD: **Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p.** *Mol Cell* 2005, **19**:123-133.

22. Pfander B, Moldovan GL, Sacher M, Hoege C, Jentsch S: **SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase.** *Nature* 2005, **436**:428-433.

23. Hong Y, Rogers R, Matunis MJ, Mayhew CN, Goodson ML, Park-Sarge OK, Sarge KD: **Regulation of heat shock transcription factor I by stress-induced SUMO-1 modification.** *J Biol Chem* 2001, **276**:40263-40267.

24. Cardone L, Hirayama J, Giordano F, Tamaru T, Palvimo JJ, Sassone-Corsi P: **Circadian clock control by SUMOylation of BMAL1.** *Science* 2005, **309**:1390-1394.

25. Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A: **c-Jun and p53 activity is modulated by SUMO-1 modification.** *J Biol Chem* 2000, **275**:13321-13329.

26. Bossis G, Malnou CE, Farras R, Andermarcher E, Hipskind R, Rodriguez M, Schmidt D, Muller S, Jariel-Encontre I, Piechaczyk M: **Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation.** *Mol Cell Biol* 2005, **25**:6964-6979.

27. Lin JY, Ohshima T, Shimotohno K: **Association of Ubc9, an E2 ligase for SUMO conjugation, with p53 is regulated by phosphorylation of p53.** *FEBS Lett* 2004, **573**:15-18.

28. Yang SH, Jaffray E, Hay RT, Sharrocks AD: **Dynamic interplay of the SUMO and ERK pathways in regulating Elk-1 transcriptional activity.** *Mol Cell* 2003, **12**:63-74.

29. Hietakangas V, Ahlskog JK, Jakobsson AM, Hellesuo M, Sahlberg NM, Holmberg CI, Mikhailov A, Palvimo JJ, Pirkkala L, Sistonen L: **Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1.** *Mol Cell Biol* 2003, **23**:2953-2968.
30. Hietakangas V, Anckar J, Blomster HA, Fujimoto M, Palvimo JJ, Nakai A, Sistonen L: **PDSM**, a motif for phosphorylation-dependent SUMO modification. *Proc Natl Acad Sci U S A* 2006, **103**:45-50.

31. Kang J, Gocke CB, Yu H: **Phosphorylation-facilitated sumoylation of MEF2C** negatively regulates its transcriptional activity. *BMC Biochem* 2006, **7**:5.

32. Gregoire S, Tremblay AM, Xiao L, Yang Q, Ma K, Nie J, Mao Z, Wu Z, Giguere V, Yang XJ: **Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation**. *J Biol Chem* 2006, **281**:4423-4433.

33. Zhao X, Sternsdorf T, Bolger TA, Evans RM, Yao TP: **Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications**. *Mol Cell Biol* 2005, **25**:8456-8464.

34. Shalizi A, Gaudilliere B, Yuan Z, Stegmuller J, Shirogane T, Ge Q, Tan Y, Schulman B, Harper JW, Bonni A: **A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation**. *Science* 2006, **311**:1012-1017.

35. Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, Suske G: **Transcription factor Sp3 is silenced through SUMO modification by PIAS1**. *Embo* J 2002, **21**:5206-5215.

36. Bouras T, Fu M, Sauve AA, Wang F, Quong AA, Perkins ND, Hay RT, Gu W, Pestell RG: **SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1**. *J Biol Chem* 2005, **280**:10264-10276.

37. Desterro JM, Rodriguez MS, Hay RT: **SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation**. *Mol Cell* 1998, **2**:233-239.

38. Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S: **Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress**. *Cell* 2003, **115**:565-576.

39. Hay RT: **Modifying NEMO**. *Nat Cell Biol* 2004, **6**:89-91.

40. Watts FZ: **Sumoylation of PCNA: Wrestling with recombination at stalled replication forks**. *DNA Repair* (Amst) 2006, **5**:399-403.

41. Ulrich HD: **Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest**. *Trends Cell Biol* 2005, **15**:525-532.

42. Sternsdorf T, Jensen K, Reich B, Will H: **The nuclear dot protein sp100, characterization of domains necessary for dimerization, subcellular localization, and modification by small ubiquitin-like modifiers**. *J Biol Chem* 1999, **274**:12555-12566.

43. Johnson ES, Gupta AA: **An E3-like factor that promotes SUMO conjugation to the yeast septins**. *Cell* 2001, **106**:735-744.

44. Muller S, Dejean A: **Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption**. *J Virol* 1999, **73**:5137-5143.

45. Ledl A, Schmidt D, Muller S: **Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor suppressor**. *Oncogene* 2005, **24**:3810-3818.

46. Parkinson J, Everett RD: **Alphaherpesvirus proteins related to herpes simplex virus type I ICP0 affect cellular structures and proteins**. *J Virol* 2000, **74**:10006-10017.

47. Boggio R, Colombo R, Hay RT, Draetta GF, Chiocca S: **A mechanism for inhibiting the SUMO pathway**. *Mol Cell* 2004, **16**:549-561.

48. Saitoh H, Hinchey J: **Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3**. *J Biol Chem* 2000, **275**:6252-6258.

49. Kurepa J, Walker JM, Smalle J, Gosink MM, Davis SJ, Durham TL, Sung DY, Vierstra RD: **The small ubiquitin-like modifier (SUMO) protein modification system in Arabidopsis. Accumulation of SUMO1 and -2 conjugates is increased by stress**. *J Biol Chem* 2003, **278**:6862-6872.

50. Zhou W, Ryan JJ, Zhou H: **Global analyses of sumoylated proteins in Saccharomyces cerevisiae. Induction of protein sumoylation by cellular stresses**. *J Biol Chem* 2004, **279**:32262-32268.

51. Manza LL, Codreanu SG, Stamer SL, Smith DL, Wells KS, Roberts RL, Liebler DC: **Global shifts in protein sumoylation in response to electrophile and oxidative stress**. *Chem Res Toxicol* 2004, **17**:1706-1715.

52. Bossis G, Melchior F: **Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes**. *Mol Cell* 2006, **21**:349-357.

53. Gius D, Botero A, Shah S, Curry HA: **Intracellular oxidation/reduction status in the regulation of transcription factors NF-kappaB and AP-1**. *Toxicol Lett* 1999, **106**:93-106.

54. Lambeth JD: **NOX enzymes and the biology of reactive oxygen**. *Nat Rev Immunol* 2004, **4**:181-189.

55. Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS, Woo HA: **Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins**. *Curr Opin Cell Biol* 2005, **17**:183-189.

56. Forman HJ, Torres M: **Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling**. *Am J Respir Crit Care Med* 2002, **166**:S4-8.

Publish with **BioMed Central** and every scientist can read your work free of charge

"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."

Sir Paul Nurse, Cancer Research UK

Your research papers will be:

• available free of charge to the entire biomedical community

• peer reviewed and published immediately upon acceptance

• cited in PubMed and archived on PubMed Central

• yours — you keep the copyright

Submit your manuscript here:
http://www.biomedcentral.com/info/publishing_adv.asp

<figure><img src="image_7.png" /></figure>

BioMedcentral