Background
The enzymes of the SUMOylation pathway play a pivotal role in a number of cellular processes including nuclear transport, signal transduction, stress responses and cell cycle progression. The covalent modification of proteins by small ubiquitin-related modifiers (SUMOs) may modulate their stability and subcellular compartmentalisation. Three classes of enzymes are involved in the process of SUMOylation; an activating enzyme (E1), conjugating enzyme (E2) and protein ligases (E3s). SAE1/SAE2 is a SUMO1, 2 and 3 E1 activating enzyme and functions as a heterodimer. Cloning of the human SAE1 and SAE2 genes was first described by Desterro et al. (1999). SAE1 and SAE2 share sequence similarity to the N-terminus and C-terminus of ubiquitin E1 activating enzymes respectively (Desterro et al. 1999). SAE2 harbours the E1-like active cysteine site while SUMO1 transfer to the E2 conjugating enzyme UBE2I requires both of the SAE subunits (Desterro et al. 1999). A crystal structure of the SAE1/SAE2 dimer together with the SUMO1 adenylate has been solved at 2.45 Ångström resolution (Olsen et al. 2010). Western blot analysis of cell-cycle synchronised HeLa cells demonstrated increased SAE1 expression in S phase followed by a decrease in G2 phase. Immunofluorescence showed that SAE1 and SAE2 were distributed throughout the nuclei but were excluded from the nucleoli (Azuma et al. 2001). A short hairpin RNA (shRNA) screen was carried out in the presence of aberrant MYC signalling to identify genes that altered the fitness of mammary epithelial cells. In this screen SAE1 and SAE2 were identified as MYC synthetic lethal genes. Upon MYC hyperactivation inactivation of SAE2 led to mitotic catastrophe and cell death and it is thought that SAE2 inactivation could be a therapeutic strategy in MYC driven cancers (Kessler et al. 2012).
References
Azuma Y, Tan SH, Cavenagh MM, Ainsztein AM, Saitoh H, et al. (2001) Expression and regulation of the mammalian SUMO-1 E1 enzyme. FASEB J 15, 1825-1827.
Desterro JM, Rodriguez MS, Kemp GD, Hay RT (1999) Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. J Biol Chem 274, 10618-10624.
Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, et al. (2012) A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335, 348-353.
Olsen SK, Capili AD, Lu X, Tan DS, Lima CD (2010) Active site remodelling accompanies thioester bond formation in the SUMO E1. Nature 463, 906-912.