The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including regulated and targeted proteasomal degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). UBE2N is a member of the E2 conjugating enzyme family and cloning of the human gene was first described by Yamaguchi et al. (1996). The human UBE2N sequence shares 80% identity with the Drosophila ‘bendless’ gene product. In yeast, UBE2N forms a specific heteromeric complex with MMS2, a signalling component of the RAD6 pathway. The RAD6 pathway is central to DNA repair and two major components of this pathway are RAD6 and the MMS2/UBE2N heterodimer which are recruited to chromatin by the RING finger proteins RAD18 and RAD5, respectively (Hofmann and Pickart, 1999). Proliferating Cell Nuclear Antigen (PCNA) is modified by lys-63-linked polyubiquitylation, which requires MMS2, UBE2N and RAD5. Depletion of UBE2N in vitro results in severe growth defects caused by chromosome instability, as well as hypersensitivity to UV and ionizing radiation, this is consistent with a conserved role for UBE2N in RAD6/RAD18-dependent post-replication repair (Zhao et al., 2007). Cytokine receptor signalling results in complex formation of protein kinases such as CD40 with TRAF2 and TRAF3, UBE2N, cellular inhibitor of apoptosis protein-1 (CIAP1) and -2 (CIAP2), IKK-α and MEKK1. Translocation of a TRAF2, UBE2N, and IKK-α complex from the membrane to the cytosol is initiated by a CIAP1/CIAP2-induced degradation of TRAF3 which results in activation of MEKK1 and MAP kinase cascades (Matsuzawa et al., 2008). Heterozygous UBE2N mice exhibit selectively impaired activation of signal transduction pathways initiated by TNFr and show reduced ubiquitylation of TRAF6. Reducing UBE2N activity may have therapeutic uses in controlling inflammatory responses (Matsuzawa et al., 2008).
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