This gene encodes a protein that is a member of the SUMO (small ubiquitin-like modifier) protein family. It functions in a manner similar to ubiquitin in that it is bound to target proteins as part of a post-translational modification system. However, unlike ubiquitin, which targets proteins for degradation, this protein is involved in a variety of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability. It is not active until the last four amino acids of the carboxy-terminus have been cleaved off. Several pseudogenes have been reported for this gene. Alternate transcriptional splice variants encoding different isoforms have been characterized.[3]
Most cleft genes have a sumoylation component .[4] Analysis of chromosomal anomalies in patients has led to the identification and confirmation of SUMO1 as a cleft lip and palate locus.[5]
Interactions
Small ubiquitin-related modifier 1 has been shown to interact with:
Heart failure is a process by which the heart’s pumping ability is significantly weakened, so that the body is unable to get adequate circulation. A weakened heart results in symptoms of fatigue, decreased exercise tolerance and shortness of breath. Patients with heart failure have a significantly increased risk of death compared to people with normal heart function. Heart failure is a major public health concern, as its incidence is on the rise worldwide, and is a leading cause of death in developed nations [23]
SUMO 1 is a key component in cardiac function, since it helps regulate calcium homeostasis in the mitochondria of heart cells. SUMO 1 is associated with another essential cardiac protein called sarco/endoplasmic reticulum Ca2+ ATPase, or SERCA2A. SERCA is a transmembrane protein located in the sarcoplasmic reticulum of cardiac cells. Its main function is to regulate the discharge and uptake of intracellular calcium between the cytosol and the lumen of the sarcoplasmic reticulum. Calcium is an essential factor for the development of cardiac myocyte contraction and relaxation. Thus, the management of intracellular calcium homeostasis by SERCA2A is critical for overall cardiac performance.[24] Normally, SUMO 1 activates and stabilizes SERCA2A by binding at lysine resides 480 and 585. The interaction between SUMO 1 and SERCA2A is crucial for regulating calcium levels inside cardiac myocytes. Reduction in SUMO 1 protein reduces SERCA2A, and thus efficient calcium handling in patients with failing hearts.[25]
As a drug target
SUMO 1 may be an important therapeutic target to help improve cardiac performance in patients with heart failure. In a mouse model, the introduction of SUMO 1 through gene therapy was associated with improved activity of SERCA2A, which resulted in improved cardiac function through an augmentation of cardiac contractility.[25] Furthermore, overexpression of SUMO 1 resulted in accelerated calcium uptake, providing further evidence regarding its importance in maintaining adequate calcium levels in heart cells. This particular heart protein may be an exciting and novel target for heart failure treatment in the future.[25]
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↑ 2.02.12.2Okura T, Gong L, Kamitani T, Wada T, Okura I, Wei CF, Chang HM, Yeh ET (November 1996). "Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin". Journal of Immunology. 157 (10): 4277–81. PMID8906799.
↑Pauws E, Stanier P (December 2007). "FGF signalling and SUMO modification: new players in the aetiology of cleft lip and/or palate". Trends in Genetics. 23 (12): 631–40. doi:10.1016/j.tig.2007.09.002. PMID17981355.
↑ 7.07.1Lin DY, Shih HM (July 2002). "Essential role of the 58-kDa microspherule protein in the modulation of Daxx-dependent transcriptional repression as revealed by nucleolar sequestration". The Journal of Biological Chemistry. 277 (28): 25446–56. doi:10.1074/jbc.M200633200. PMID11948183.
↑ 8.08.1Ryu SW, Chae SK, Kim E (December 2000). "Interaction of Daxx, a Fas binding protein, with sentrin and Ubc9". Biochemical and Biophysical Research Communications. 279 (1): 6–10. doi:10.1006/bbrc.2000.3882. PMID11112409.
↑ 9.09.1Ivanchuk SM, Mondal S, Rutka JT (June 2008). "p14ARF interacts with DAXX: effects on HDM2 and p53". Cell Cycle. 7 (12): 1836–50. doi:10.4161/cc.7.12.6025. PMID18583933.
↑Kang ES, Park CW, Chung JH (December 2001). "Dnmt3b, de novo DNA methyltransferase, interacts with SUMO-1 and Ubc9 through its N-terminal region and is subject to modification by SUMO-1". Biochemical and Biophysical Research Communications. 289 (4): 862–8. doi:10.1006/bbrc.2001.6057. PMID11735126.
↑ 11.011.111.2Minty A, Dumont X, Kaghad M, Caput D (November 2000). "Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif". The Journal of Biological Chemistry. 275 (46): 36316–23. doi:10.1074/jbc.M004293200. PMID10961991.
↑Lee BH, Yoshimatsu K, Maeda A, Ochiai K, Morimatsu M, Araki K, Ogino M, Morikawa S, Arikawa J (December 2003). "Association of the nucleocapsid protein of the Seoul and Hantaan hantaviruses with small ubiquitin-like modifier-1-related molecules". Virus Research. 98 (1): 83–91. doi:10.1016/j.virusres.2003.09.001. PMID14609633.
↑Kahyo T, Nishida T, Yasuda H (September 2001). "Involvement of PIAS1 in the sumoylation of tumor suppressor p53". Molecular Cell. 8 (3): 713–8. doi:10.1016/S1097-2765(01)00349-5. PMID11583632.
↑Kamitani T, Nguyen HP, Kito K, Fukuda-Kamitani T, Yeh ET (February 1998). "Covalent modification of PML by the sentrin family of ubiquitin-like proteins". The Journal of Biological Chemistry. 273 (6): 3117–20. doi:10.1074/jbc.273.6.3117. PMID9452416.
↑ 15.015.1Tatham MH, Kim S, Yu B, Jaffray E, Song J, Zheng J, Rodriguez MS, Hay RT, Chen Y (August 2003). "Role of an N-terminal site of Ubc9 in SUMO-1, -2, and -3 binding and conjugation". Biochemistry. 42 (33): 9959–69. doi:10.1021/bi0345283. PMID12924945.
↑Gong L, Li B, Millas S, Yeh ET (April 1999). "Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex". FEBS Letters. 448 (1): 185–9. doi:10.1016/S0014-5793(99)00367-1. PMID10217437.
↑Wang YT, Chuang JY, Shen MR, Yang WB, Chang WC, Hung JJ (July 2008). "Sumoylation of specificity protein 1 augments its degradation by changing the localization and increasing the specificity protein 1 proteolytic process". Journal of Molecular Biology. 380 (5): 869–85. doi:10.1016/j.jmb.2008.05.043. PMID18572193.
↑Liou ML, Liou HC (April 1999). "The ubiquitin-homology protein, DAP-1, associates with tumor necrosis factor receptor (p60) death domain and induces apoptosis". The Journal of Biological Chemistry. 274 (15): 10145–53. doi:10.1074/jbc.274.15.10145. PMID10187798.
↑ 20.020.1Mao Y, Desai SD, Liu LF (August 2000). "SUMO-1 conjugation to human DNA topoisomerase II isozymes". The Journal of Biological Chemistry. 275 (34): 26066–73. doi:10.1074/jbc.M001831200. PMID10862613.
↑Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC1847948. PMID17353931.
↑Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ (October 1996). "Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system". Genomics. 37 (2): 183–6. doi:10.1006/geno.1996.0540. PMID8921390.
↑Schwartz RJ, Yeh ET (2012). "Weighing in on heart failure: the role of SERCA2a SUMOylation". Circulation Research. 110 (2): 198–9. doi:10.1161/RES.0b013e318246f187. PMID22267837.
↑Periasamy M, Huke S (2001). "SERCA pump level is a critical determinant of Ca(2+)homeostasis and cardiac contractility". Journal of Molecular and Cellular Cardiology. 33 (6): 1053–63. doi:10.1006/jmcc.2001.1366. PMID11444913.
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Liou ML, Liou HC (April 1999). "The ubiquitin-homology protein, DAP-1, associates with tumor necrosis factor receptor (p60) death domain and induces apoptosis". The Journal of Biological Chemistry. 274 (15): 10145–53. doi:10.1074/jbc.274.15.10145. PMID10187798.
