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研究生： 謝鎔聲
HSIEH, JUNG-SHENG
論文名稱： 人類粒線體第一蛋白質複合體NDUFS7次單元Sumoylation修飾及對其在細胞內分佈之影響
Sumoylation of human mitochondrial NADH dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7) and the effect on its subcellular localization
指導教授： 高茂傑
Kao, Mou-Chieh
口試委員: 張壯榮
Chang, Chuang-Rung
林立元
Lin, Lih-Yuan
學位類別： 碩士
Master
系所名稱： 生命科學暨醫學院 - 分子醫學研究所
Institute of Molecular Medicine
論文出版年： 2019
畢業學年度： 107
語文別： 英文
論文頁數： 64
中文關鍵詞： 粒線體 、次單元 、修飾 、分佈
外文關鍵詞： subunit
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    • 粒線體在真核細胞中的主要功能為提供生物體所需的能量。人類粒線體第一蛋白質複合體是由44個次單元蛋白所組成，其中的一個次單元NDUFS7為細胞核所編碼的，並且為此複合體中的電子傳遞鏈提供了最後一個鐵硫中心N2。之前，我們驗證了在NDUFS7的N端帶有粒線體標的序列(mitochondrial targeting sequence, MTS) ，而在靠近NDUFS7的C端的部分則帶有細胞和導入序列(nuclear localization signal, NLS)及細胞核導出序列(nuclear export signal, NES)。類小泛素化(SUMOylation)是一種可逆的轉譯後修飾,並會在目標蛋白上接上類小泛素蛋白(small ubiquitin-like modifier, SUMO)。它是一種負責調控細胞內多種生理反應的關鍵修飾作用。在之前的研究中發現，NDUFS7可以被類小泛素蛋白SUMO1及其旁系SUMO3所修飾。在本篇研究中，我們試著探討NDUFS7被SUMO蛋白修飾後在細胞中的分佈。在正常情況下，NDUFS7以未成熟以及成熟的形式出現在粒線體，另外還會有一部分未成熟的NDUFS7出現在細胞核。不過，當NDUFS7被SUMO修飾後，可以看到多種形式的NDUFS7-SUMO1和NDUFS7-SUMO3在細胞核中出現。有趣的是，在SUMO1修飾的組別中未成熟的NDUFS7在細胞核中的量有了明顯的增加。我們認為NDUFS7被SUMO1修飾後似乎會促進它進細胞核而SUMO3的修飾則不具此功能。此外，我們還比較了在缺氧及氧化壓力的條件下,未成熟、成熟以及SUMO修飾的NDUFS7在細胞中的分佈。雖然，氯化鈷(CoCl2)誘導的缺氧狀態下皆有一種形式的NDUFS7-SUMO1和NDFUS7-SUMO3出現在粒線體。不過，粒線體中未成熟及成熟的NDUFS7則沒有的顯著改變。相反的，SUMO3修飾的組別中細胞核內未成熟的NDUFS7及NDUFS7-SUMO3皆減少了，然而此現象卻沒在SUMO1修飾的組別中發現到。在H2O2所誘導的氧化壓力的實驗中，SUMO1的組別氧化壓力對其沒有特別的影響，不過氧化壓力卻對SUMO3的組別有顯著的影響。細胞核中不單是NDUFS7-SUMO3的量大幅度的減少，且未成熟NDUFS7的量也減少了。根據本篇的研究結果，我們認為在正常的情況下SUMO1的修飾對NDUFS7有促進其進入細胞核的功能，而SUMO3的修飾則無。然而在缺氧及氧化壓力下，SUMO3對NDUFS7的修飾反而會減少其在細胞核出現。其詳細的生理意義仍需要更進一步地去探討。令人失望的是，由於我們缺少靈敏可靠的NDUFS7抗體導致我們並沒有在內源性的實驗中發現被SUMO修飾的內生性NDUFS7。

    Mitochondria are well recognized for energy production in eukaryotic cells. Human NADH dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7) is a nuclear-encoded core protein in mitochondrial respiratory complex I (NADH:ubiquinone oxidoreductase) which is made up of 44 different subunits. It contains an iron-sulfur cluster N2 (a [4Fe-4S] cluster), a final redox center for electron transfer in complex I. We previously identified that NDUFS7 has a mitochondrial targeting sequence (MTS) at the N-terminu’s and a nuclear localization signal (NLS) and a nuclear export signal (NES) at the C-terminus of the protein. SUMOylation is a reversible post-translational modification which can conjugate a small ubiquitin-like modifier (SUMO) on the target protein. SUMOylation has been considered as a key modification in modulating many cellular processes. In previous studies, we have shown that NDUFS7 could be modified by both SUMO1 and SUMO2/3. In this study, we tried to explore the localiztion of NDUFS7 after SUMOylation in cells. Normally, NDUFS7 is present in mitochondria as the precursor form and the mature form, and a small amount of the precursor form of NDUFS7 was found in the nucleus. However, after SUMOylation, multiple forms of NDUFS7-SUMO1 and NDUFS7-SUMO3 were observed in the nucleus. Interestingly, the precursor form of NDUFS7 in the SUMO1-modified group was also increased significantly in the nucleus, suggesting that modification with SUMO1 is likely to promote nuclear localization of NDUFS7 but not with SUMO3. In addition, we also compared the localization of the precursor, the mature and the SUMOylated form of NDUFS7 under hypoxia and oxidative stress. Although SUMOylation promoted the presence of a form of NDUFS7-SUMO1 and NDUFS7-SUMO3 in mitochondria under treatment of hypoxia-mimicking reagent CoCl2, the amount of mitochondrial localization of NDUFS7 was not changed. In contrast, both the SUMOylated forms and the precursor form of NDUFS7 were decreased in the nucleus in the SUMO3-modified group but not in the SUMO1-modified group. Oxidative stress induced by H2O2 treatment did not have a significant effect on the modificaiton of NDUFS7 with SUMO1 and its localizaiton. However, the same oxidative stress not only decreased the level of SUMO3-conjugated NDUFS7 but also reduced the NDUFS7 precursor in the nucleus. Our findings suggest that modification with SUMO1, not SUMO3, normally contributes to the nuclear localization of NDUFS7. However, under hypoxia or oxidative stress, the nuclear localization of NDUFS7 is significantly reduced in the SUMO3 modification condition. The detailed biological meaning of these phenomena need to further verify. Unfortunately, because of a lack of a reliable antibody against NDUFS7, SUMOylaiton of NDUFS7 was not observed in vivo.

    Table of contents 中文摘要.............................................................................................................. I Abstract .............................................................................................................III Abbreviations ...................................................................................................XI Introduction ....................................................................................................... 1 1. Mitochondria ............................................................................................. 1 1-1 Mitochondrial genome .....................................................................................2 1-2 Oxidative phosphorylation (OXPHOS) system ...............................................3 1-3 The crosstalk between mitochondria and nuclei ..............................................4 1-4 The crosstalk between mitochondria and endoplasmic reticula (ER) ..............5 1-5 Mitochondrial complex I (NADH: ubiquinone oxidoreductase) .....................6 1-6 Human NADH dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7) ........7 1-7 The association between NDUFS7 and diseases .............................................8 2. SUMOylation ..................................................................................................9 2-1 Small ubiquitin-like modifier (SUMO) proteins ............................................10 2-2 The SUMO pathway ......................................................................................10 2-3 SUMO binding sites and conjugation forms ..................................................11 2-3-1 SUMO binding motif ..............................................................................11 2-3-2 SUMO conjugation forms ......................................................................13 2-4 The effects of SUMOylation and its biological significance .........................14 2-4-1 Sumoylation and genomic homeostasis ..................................................14 2-4-2 SUMOylation and protein translocation .................................................15 2-4-3 SUMOylation and stresses ......................................................................16 2-4-3-1 SUMOylation and hypoxia ..............................................................16 2-4-3-2 SUMOylation and oxidative stress ..................................................17 2-5 SUMOylation in mitochondria .......................................................................17 The objective of this study ...............................................................................19 Materials and methods .....................................................................................20 Results ................................................................................................................26 1. NDUFS7 is modified by SUMO1 and SUMO3 ................................................. 26 2. The effects of modification with SUMO1, or SUMO3 for nuclear translocation of NDUFS7 are different.............................................................................................. 26 3. The treatment of hypoxia-mimicking reagent CoCl2 is likely to promote mitochondrial localization of SUMO1-conjugated NDUFS7 ................................. 27 4. The treatment of oxidative stress-inducing reagent H2O2 does not have a significant effect on the modification of NDUFS7 with SUMO1 and its subcellular localization .............................................................................................................. 28 5. The treatment of hypoxia-mimicking reagent CoCl2 is likely to reduce nuclear localization of NDUFS7 precursor but promote mitochondrial localization of SUMO3-conjugated NDUFS7................................................................................. 29 6. Oxidative stress not only decreases the level of SUMO3-conjugated NDUFS7 but also reduces the nuclear location of NDUFS7 precursor................................... 30 7. The identification of endogenous NDUFS7 and its subcellular distribution........30 8. SUMOylated-NDUFS7 was not found in cells in native conditions................... 31 Discussion ......................................................................................................... 32 1. NDUFS7 and its SUMOylation............................................................................32 2. NDUFS7 modification with SUMOs under various stresses...............................33 2-1 The connection between SUMOylation of NDUFS7 and hypoxia.............33 2-2 The connection between SUMOylation of NDUFS7 and oxidative stress..35 3. Poly-SUMOylation with SUMO1.........................................................................36 4. Some techniques needed to be involved in this study...........................................37 5. The crosstalk between SUMOylation an phosphorylation...................................37 6. The limitation of endogenous NDUFS7...............................................................38 7. The NDUFS7 knockdown cell lines.....................................................................38 Table ................................................................................................................. 39 Figures............................................................................................................... 40 Reference .......................................................................................................... 52 Appendixes ....................................................................................................... 59

    References

    1. Taylor, R. W., and Turnbull, D. M. (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6, 389-402
    2. Andersson, S. G., Karlberg, O., Canbäck, B., and Kurland, C. G. (2003) On the origin of mitochondria: a genomics perspective. Philos Trans R Soc Lond B Biol Sci 358, 165-177; discussion 177-169
    3. Cogliati, S., Enriquez, J. A., and Scorrano, L. (2016) Mitochondrial Cristae: Where Beauty Meets Functionality. Trends Biochem Sci 41, 261-273
    4. van der Bliek, A. M., Sedensky, M. M., and Morgan, P. G. (2017) Cell Biology of the Mitochondrion. Genetics 207, 843-871
    5. Sazanov, L. A. (2015) A giant molecular proton pump: structure and mechanism of respiratory complex I. Nature reviews. Molecular cell biology 16, 375-388
    6. Letts, J. A., and Sazanov, L. A. (2017) Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain. Nat Struct Mol Biol 24, 800-808
    7. Maranzana, E., Barbero, G., Falasca, A. I., Lenaz, G., and Genova, M. L. (2013) Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. Antioxid Redox Signal 19, 1469-1480
    8. Brieger, K., Schiavone, S., Miller, F. J., Jr., and Krause, K. H. (2012) Reactive oxygen species: from health to disease. Swiss Med Wkly 142, w13659
    9. Monaghan, R. M., Barnes, R. G., Fisher, K., Andreou, T., Rooney, N., Poulin, G. B., and Whitmarsh, A. J. (2015) A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity. Nature cell biology 17, 782-792
    10. Nargund, A. M., Pellegrino, M. W., Fiorese, C. J., Baker, B. M., and Haynes, C. M. (2012) Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science (New York, N.Y.) 337, 587-590
    11. Nargund, A. M., Fiorese, C. J., Pellegrino, M. W., Deng, P., and Haynes, C. M. (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Molecular cell 58, 123-133
    12. Giacomello, M., and Pellegrini, L. (2016) The coming of age of the mitochondria-ER contact: a matter of thickness. Cell death and differentiation 23, 1417-1427
    13. Lahiri, S., Chao, J. T., Tavassoli, S., Wong, A. K., Choudhary, V., Young, B. P., Loewen, C. J., and Prinz, W. A. (2014) A conserved endoplasmic reticulum membrane protein complex (EMC) facilitates phospholipid transfer from the ER to mitochondria. PLoS biology 12, e1001969
    14. Filadi, R., Theurey, P., and Pizzo, P. (2017) The endoplasmic reticulum-mitochondria coupling in health and disease: Molecules, functions and significance. Cell calcium 62, 1-15
    15. Sreekumar, P. G., Hinton, D. R., and Kannan, R. (2017) Endoplasmic reticulum-mitochondrial crosstalk: a novel role for the mitochondrial peptide humanin. Neural regeneration research 12, 35-38
    16. Wirth, C., Brandt, U., Hunte, C., and Zickermann, V. (2016) Structure and function of mitochondrial complex I. Biochimica et biophysica acta 1857, 902-914
    17. Vinothkumar, K. R., Zhu, J., and Hirst, J. (2014) Architecture of mammalian respiratory complex I. Nature 515, 80-84
    18. Hinchliffe, P., and Sazanov, L. A. (2005) Organization of iron-sulfur clusters in respiratory complex I. Science (New York, N.Y.) 309, 771-774
    19. Hyslop, S. J., Duncan, A. M., Pitkanen, S., and Robinson, B. H. (1996) Assignment of the PSST subunit gene of human mitochondrial complex I to chromosome 19p13. Genomics 37, 375-380
    20. Ohnishi, T. (1998) Iron-sulfur clusters/semiquinones in complex I. Biochimica et biophysica acta 1364, 186-206
    21. Hirst, J., Carroll, J., Fearnley, I. M., Shannon, R. J., and Walker, J. E. (2003) The nuclear encoded subunits of complex I from bovine heart mitochondria. Biochimica et biophysica acta 1604, 135-150
    22. Leigh, D. (1951) Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 14, 216-221
    23. Triepels, R. H., van den Heuvel, L. P., Loeffen, J. L., Buskens, C. A., Smeets, R. J., Rubio Gozalbo, M. E., Budde, S. M., Mariman, E. C., Wijburg, F. A., Barth, P. G., Trijbels, J. M., and Smeitink, J. A. (1999) Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I. Ann Neurol 45, 787-790
    24. Loeffen, J., Smeitink, J., Triepels, R., Smeets, R., Schuelke, M., Sengers, R., Trijbels, F., Hamel, B., Mullaart, R., and van den Heuvel, L. (1998) The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet 63, 1598-1608
    25. Andreazza, A. C., Wang, J. F., Salmasi, F., Shao, L., and Young, L. T. (2013) Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder. J Neurochem 127, 552-561
    26. Machado, A. K., Andreazza, A. C., da Silva, T. M., Boligon, A. A., do Nascimento, V., Scola, G., Duong, A., Cadona, F. C., Ribeiro, E. E., and da Cruz, I. B. (2016) Neuroprotective Effects of Acai (Euterpe oleracea Mart.) against Rotenone In Vitro Exposure. Oxid Med Cell Longev 2016, 8940850
    27. Meluh, P. B., and Koshland, D. (1995) Evidence that the MIF2 gene of Saccharomyces cerevisiae encodes a centromere protein with homology to the mammalian centromere protein CENP-C. Mol Biol Cell 6, 793-807
    28. Shen, Z., Pardington-Purtymun, P. E., Comeaux, J. C., Moyzis, R. K., and Chen, D. J. (1996) UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins. Genomics 36, 271-279
    29. Okura, T., Gong, L., Kamitani, T., Wada, T., Okura, I., Wei, C. F., Chang, H. M., and Yeh, E. T. (1996) Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin. J Immunol 157, 4277-4281
    30. Boddy, M. N., Howe, K., Etkin, L. D., Solomon, E., and Freemont, P. S. (1996) PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene 13, 971-982
    31. Mahajan, R., Delphin, C., Guan, T., Gerace, L., and Melchior, F. (1997) A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell 88, 97-107
    32. Ayaydin, F., and Dasso, M. (2004) Distinct in vivo dynamics of vertebrate SUMO paralogues. Mol Biol Cell 15, 5208-5218
    33. Flotho, A., and Melchior, F. (2013) Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem 82, 357-385
    34. Owerbach, D., McKay, E. M., Yeh, E. T., Gabbay, K. H., and Bohren, K. M. (2005) A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation. Biochem Biophys Res Commun 337, 517-520
    35. Guo, D., Han, J., Adam, B. L., Colburn, N. H., Wang, M. H., Dong, Z., Eizirik, D. L., She, J. X., and Wang, C. Y. (2005) Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. Biochem Biophys Res Commun 337, 1308-1318
    36. Wei, W., Yang, P., Pang, J., Zhang, S., Wang, Y., Wang, M. H., Dong, Z., She, J. X., and Wang, C. Y. (2008) A stress-dependent SUMO4 sumoylation of its substrate proteins. Biochem Biophys Res Commun 375, 454-459
    37. Xu, Z., and Au, S. W. (2005) Mapping residues of SUMO precursors essential in differential maturation by SUMO-specific protease, SENP1. The Biochemical journal 386, 325-330
    38. Johnson, E. S., Schwienhorst, I., Dohmen, R. J., and Blobel, G. (1997) The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer. The EMBO journal 16, 5509-5519
    39. Desterro, J. M., Thomson, J., and Hay, R. T. (1997) Ubch9 conjugates SUMO but not ubiquitin. FEBS Lett 417, 297-300
    40. Rabellino, A., Andreani, C., and Scaglioni, P. P. (2017) The Role of PIAS SUMO E3-Ligases in Cancer. Cancer Res 77, 1542-1547
    41. Hickey, C. M., Wilson, N. R., and Hochstrasser, M. (2012) Function and regulation of SUMO proteases. Nature reviews. Molecular cell biology 13, 755-766
    42. Zunino, R., Schauss, A., Rippstein, P., Andrade-Navarro, M., and McBride, H. M. (2007) The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. J Cell Sci 120, 1178-1188
    43. Matic, I., Schimmel, J., Hendriks, I. A., van Santen, M. A., van de Rijke, F., van Dam, H., Gnad, F., Mann, M., and Vertegaal, A. C. (2010) Site-specific identification of SUMO-2 targets in cells reveals an inverted SUMOylation motif and a hydrophobic cluster SUMOylation motif. Molecular cell 39, 641-652
    44. Hietakangas, V., Anckar, J., Blomster, H. A., Fujimoto, M., Palvimo, J. J., Nakai, A., and Sistonen, L. (2006) PDSM, a motif for phosphorylation-dependent SUMO modification. Proceedings of the National Academy of Sciences of the United States of America 103, 45-50
    45. Yang, S. H., Galanis, A., Witty, J., and Sharrocks, A. D. (2006) An extended consensus motif enhances the specificity of substrate modification by SUMO. The EMBO journal 25, 5083-5093
    46. Picard, N., Caron, V., Bilodeau, S., Sanchez, M., Mascle, X., Aubry, M., and Tremblay, A. (2012) Identification of estrogen receptor β as a SUMO-1 target reveals a novel phosphorylated sumoylation motif and regulation by glycogen synthase kinase 3β. Molecular and cellular biology 32, 2709-2721
    47. Gareau, J. R., and Lima, C. D. (2010) The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nature reviews. Molecular cell biology 11, 861-871
    48. Kerscher, O. (2007) SUMO junction-what's your function? New insights through SUMO-interacting motifs. EMBO reports 8, 550-555
    49. Praefcke, G. J., Hofmann, K., and Dohmen, R. J. (2012) SUMO playing tag with ubiquitin. Trends Biochem Sci 37, 23-31
    50. Kaur, K., Park, H., Pandey, N., Azuma, Y., and De Guzman, R. N. (2017) Identification of a new small ubiquitin-like modifier (SUMO)-interacting motif in the E3 ligase PIASy. The Journal of biological chemistry 292, 10230-10238
    51. Tatham, M. H., Jaffray, E., Vaughan, O. A., Desterro, J. M., Botting, C. H., Naismith, J. H., and Hay, R. T. (2001) Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. The Journal of biological chemistry 276, 35368-35374
    52. Harder, Z., Zunino, R., and McBride, H. (2004) Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Current biology : CB 14, 340-345
    53. Blomster, H. A., Imanishi, S. Y., Siimes, J., Kastu, J., Morrice, N. A., Eriksson, J. E., and Sistonen, L. (2010) In vivo identification of sumoylation sites by a signature tag and cysteine-targeted affinity purification. The Journal of biological chemistry 285, 19324-19329
    54. Bruderer, R., Tatham, M. H., Plechanovova, A., Matic, I., Garg, A. K., and Hay, R. T. (2011) Purification and identification of endogenous polySUMO conjugates. EMBO reports 12, 142-148
    55. Hsiao, H. H., Meulmeester, E., Frank, B. T., Melchior, F., and Urlaub, H. (2009) "ChopNSpice," a mass spectrometric approach that allows identification of endogenous small ubiquitin-like modifier-conjugated peptides. Molecular & cellular proteomics : MCP 8, 2664-2675
    56. Wagner, T., Kiweler, N., Wolff, K., Knauer, S. K., Brandl, A., Hemmerich, P., Dannenberg, J. H., Heinzel, T., Schneider, G., and Kramer, O. H. (2015) Sumoylation of HDAC2 promotes NF-kappaB-dependent gene expression. Oncotarget 6, 7123-7135
    57. Lombardi, P. M., Matunis, M. J., and Wolberger, C. (2017) RAP80, ubiquitin and SUMO in the DNA damage response. Journal of molecular medicine (Berlin, Germany) 95, 799-807
    58. Kolesar, P., Altmannova, V., Silva, S., Lisby, M., and Krejci, L. (2016) Pro-recombination Role of Srs2 Protein Requires SUMO (Small Ubiquitin-like Modifier) but Is Independent of PCNA (Proliferating Cell Nuclear Antigen) Interaction. The Journal of biological chemistry 291, 7594-7607
    59. Enserink, J. M. (2015) Sumo and the cellular stress response. Cell division 10, 4
    60. Feng, L., Lin, T., Uranishi, H., Gu, W., and Xu, Y. (2005) Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Molecular and cellular biology 25, 5389-5395
    61. Ashikari, D., Takayama, K., Tanaka, T., Suzuki, Y., Obinata, D., Fujimura, T., Urano, T., Takahashi, S., and Inoue, S. (2017) Androgen induces G3BP2 and SUMO-mediated p53 nuclear export in prostate cancer. Oncogene 36, 6272-6281
    62. Choi, S. G., Kim, H., Jeong, E. I., Lee, H. J., Park, S., Lee, S. Y., Lee, H. J., Lee, S. W., Chung, C. H., and Jung, Y. K. (2017) SUMO-Modified FADD Recruits Cytosolic Drp1 and Caspase-10 to Mitochondria for Regulated Necrosis. Molecular and cellular biology 37
    63. Guo, C., and Henley, J. M. (2014) Wrestling with stress: roles of protein SUMOylation and deSUMOylation in cell stress response. IUBMB life 66, 71-77
    64. Saitoh, H., and Hinchey, J. (2000) Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. The Journal of biological chemistry 275, 6252-6258
    65. Ciria, M., García, N. A., Ontoria-Oviedo, I., González-King, H., Carrero, R., De La Pompa, J. L., Montero, J. A., and Sepúlveda, P. (2017) Mesenchymal Stem Cell Migration and Proliferation Are Mediated by Hypoxia-Inducible Factor-1α Upstream of Notch and SUMO Pathways. Stem cells and development 26, 973-985
    66. Bossis, G., and Melchior, F. (2006) Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Molecular cell 21, 349-357
    67. Heras, G., Namuduri, A. V., Traini, L., Shevchenko, G., Falk, A., Bergstrom Lind, S., Mi, J., Tian, G., and Gastaldello, S. (2018) Muscle RING-finger protein-1 (MuRF1) functions and cellular localization are regulated by SUMO1 post-translational modification. Journal of molecular cell biology
    68. Chen, H., and Chan, D. C. (2005) Emerging functions of mammalian mitochondrial fusion and fission. Human molecular genetics 14 Spec No. 2, R283-289
    69. Prudent, J., Zunino, R., Sugiura, A., Mattie, S., Shore, G. C., and McBride, H. M. (2015) MAPL SUMOylation of Drp1 Stabilizes an ER/Mitochondrial Platform Required for Cell Death. Molecular cell 59, 941-955
    70. Comerford, K. M., Leonard, M. O., Karhausen, J., Carey, R., Colgan, S. P., and Taylor, C. T. (2003) Small ubiquitin-related modifier-1 modification mediates resolution of CREB-dependent responses to hypoxia. Proceedings of the National Academy of Sciences of the United States of America 100, 986-991
    71. Messner, S., Schuermann, D., Altmeyer, M., Kassner, I., Schmidt, D., Schar, P., Muller, S., and Hottiger, M. O. (2009) Sumoylation of poly(ADP-ribose) polymerase 1 inhibits its acetylation and restrains transcriptional coactivator function. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23, 3978-3989
    72. Sang, J., Yang, K., Sun, Y., Han, Y., Cang, H., Chen, Y., Shi, G., Wang, K., Zhou, J., Wang, X., and Yi, J. (2011) SUMO2 and SUMO3 transcription is differentially regulated by oxidative stress in an Sp1-dependent manner. The Biochemical journal 435, 489-498
    73. Huang, C., Han, Y., Wang, Y., Sun, X., Yan, S., Yeh, E. T., Chen, Y., Cang, H., Li, H., Shi, G., Cheng, J., Tang, X., and Yi, J. (2009) SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation. The EMBO journal 28, 2748-2762
    74. Yang, M., Hsu, C. T., Ting, C. Y., Liu, L. F., and Hwang, J. (2006) Assembly of a polymeric chain of SUMO1 on human topoisomerase I in vitro. J Biol Chem 281, 8264-8274
    75. Zhang, D., Liang, Y., Xie, Q., Gao, G., Wei, J., Huang, H., Li, J., Gao, J., and Huang, C. (2015) A novel post-translational modification of nucleolin, SUMOylation at Lys-294, mediates arsenite-induced cell death by regulating gadd45alpha mRNA stability. The Journal of biological chemistry 290, 4784-4800

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