RING finger, H2 subclass, found in ubiquitin-protein ligase E3-alpha-2 (UBR2) and similar proteins
UBR2, also known as N-recognin-2 or E3alpha-II, is an E3 ubiquitin-protein ligase that play an important role in maintaining genome integrity and in homologous recombination repair. It regulates the level of the transcription factor Rpn4 (also known as Son1 and Ufd5) through ubiquitylation. The ubiquitin-conjugating enzyme Rad6, another binding partner of URB2, and an additional factor Mub1, are required for the ubiquitin-dependent degradation of Rpn4. UBR2 associates with Mub1 to form a Mub1/Ubr2 ubiquitin ligase complex that regulates the conserved Dsn1 kinetochore protein levels, which is a part of a quality control system that monitors kinetochore integrity, thus ensuring genomic stability. As the recognition component of a major cellular proteolytic system, UBR2 is associated with chromatin and controls chromatin dynamics and gene expression in both spermatocytes and somatic cells. Moreover, UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination. It functions as a scaffold E3 promoting HR6B/UbcH2-dependent ubiquitylation of H2A and H2B, but not H3 and H4. It also binds to Tex19.1, also known as Tex19, a germ cell-specific protein, and metabolically stabilizes it during spermatogenesis. Furthermore, UBR2 is involved in skeletal muscle (SKM) atrophy. Its expression can be modulated by the mouse ether-a-gogo-related gene 1a (MERG1a) potassium channel. In addition, UBR2 up-regulation in cachectic muscle is mediated by the p38beta-CCAAT/enhancer binding protein (C/EBP)-beta signaling pathway responsible for the bulk of tumor-induced muscle proteolysis. UBR2 contains an N-terminal ubiquitin-recognin (UBR) box involved in binding type-1 (basic) N-end rule substrate, an N-domain (also known as ClpS domain) required for type-2 (bulky hydrophobic) N-end rule substrate recognition, a C3H2C3-type RING-H2 finger, and a C-terminal UBR-specific autoinhibitory (UAIN) domain.