UBE2R2 is an E2 ubiquitin-conjugating enzyme that functions as a critical component of the ubiquitin-proteasome system. The enzyme accepts ubiquitin from E1 activating enzymes and catalyzes its covalent attachment to target proteins via E3 ligase complexes 1. UBE2R2 demonstrates intrinsic programming for polyubiquitination, particularly through Lys-48 linkages, and can perform monoubiquitination in vitro 1. The enzyme works in collaboration with various cullin-RING ligase (CRL) complexes, showing specific pairing with CUL2-based CRLs that is essential for efficient PROTAC-induced substrate degradation 1. Despite its polyubiquitination capabilities, CUL2 employs UBE2R2 for geometrically precise substrate priming and rapid ubiquitination of diverse receptor-recruited substrates 1. Interestingly, UBE2R2 exhibits negligible ubiquitylation activity at physiological concentrations when functioning alone, and its ablation does not significantly affect SCF substrate stability in cells, suggesting functional redundancy with other E2 enzymes like UBE2G1 2. The human SCF system demonstrates diversification through association with multiple catalytic enzyme partners, including UBE2R2, which contributes to robust cullin-RING ligase function through multiplicity of polyubiquitylation pathways 2.