Disease relevance of UBE2N

• Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas [1].

High impact information on UBE2N

• The E2 ubiquitin-conjugating enzyme UBE2N was a preferential binding partner of the 'weak' STK15 Phe31 variant form in yeast two-hybrid screens and in human cells [2].
• We find that TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin [3].
• The Ubc13 E2 ubiquitin-conjugating enzyme is key in the process of 'tagging' target proteins with lysine 63-linked polyubiquitin chains, which are essential for the transmission of immune receptor signals culminating in activation of the transcription factor NF-kappaB [4].
• Here we demonstrate that conditional ablation of Ubc13 resulted in defective B cell development and in impaired B cell and macrophage activation [4].
• In response to all tested stimuli except tumor necrosis factor, Ubc13-deficient cells showed almost normal NF-kappaB activation but considerably impaired activation of mitogen-activated protein kinase [4].

Biological context of UBE2N

• This interaction results in colocalization of UBE2N with STK15 at the centrosomes during mitosis [2].
• A heterodimer composed of the catalytically active ubiquitin-conjugating enzyme hUbc13 and its catalytically inactive paralogue, hMms2, forms the catalytic core for the synthesis of an alternative type of multiubiquitin chain where ubiquitin molecules are tandemly linked to one another through a Lys-63 isopeptide bond [5].
• Although the ubiquitin ligase activity of CHIP requires its dimerization through the U box domain, the crystal structure of the CHIP-E2 complex reveals that the protomers in the CHIP homodimer adopt distinct conformations such that only one U box of CHIP interacts with Ubc13 [6].
• In response to DNA damage, Ubc13 is no longer capable of facilitating p53 monomerization, in part due to a decrease in its own levels which is p53 dependent [7].
• In addition, PMA/ionophore-mediated ubiquitination of NF-kappaB essential modulator (NEMO)/IkappaB kinase gamma (IKKgamma) and phosphorylation of TGF-beta-activated kinase 1 (TAK1) were nearly abolished in Ubc13-deficient thymocytes [8].

Anatomical context of UBE2N

• Significantly, wild-type but not mutant Ubc13 is associated with polysomes and enriches p53 within this fraction [7].
• The frequency of T lymphocytes was severely reduced in spleens from Ubc13-deficient mice [8].
• In these tumor cell lines, BLU expression was restored after treatment with a demethylating agent [1].
• In cell lines, a correlation with lack of expression was evident for RASSF1A, but less clear for NORE1A, BLU and CASP8 [9].

Associations of UBE2N with chemical compounds

• These were histidine triad nucleotide-binding protein (HINT), ubiquitin conjugating enzyme E2N (UBE2N) and glutamate receptor, ionotropic, AMPA 2 (GRIA2) [10].
• When BLU/ZMYND10 is expressed in the absence of doxycycline, the stable transfectants were able to induce tumor suppression in nude mice [11].
• In the current study, a gene inactivation test (GIT) utilizing a tetracycline regulation system was used to study the functional role of BLU/ZMYND10 [11].

Physical interactions of UBE2N

• Aurora-A in a complex with UBE2N/MMS2 catalyses polyubiquitination of IkappaBalpha in vitro and in vivo [12].

Other interactions of UBE2N

• Nuclear magnetic resonance (NMR) spectroscopy was used to determine the solution state structure of the RING domain from human TRAF6, and the interaction between hUbc13 and TRAF6 was characterized using NMR chemical shift mapping [13].
• Furthermore, short interfering RNAs that reduced the expression of paracaspase and UBC13 abrogated the effects of Bcl10 [14].
• Here we report the crystal structure of a complex between hMms2 (Uev1) and hUbc13 at 1.85 A resolution and a structure of free hMms2 at 1.9 A resolution [15].
• ISG15 modification of ubiquitin E2 Ubc13 disrupts its ability to form thioester bond with ubiquitin [16].
• The RING finger protein RNF8 recruits UBC13 for lysine 63-based self polyubiquitylation [17].

Analytical, diagnostic and therapeutic context of UBE2N

• Furthermore, a dissociation constant of 49 +/- 7 nM was determined for the interaction between Mms2 and Ubc13 using isothermal titration calorimetry [18].
• The method proposed is based on the processing of the residual terms resulting from the BLUP methodology applied to an additive animal model [19].

References