Model of the roles of UBE2G1 and SENP8 in CM toxicity. We hypothesize that UBE2G1 is the preferred E2 Ub conjugating enzyme for polyubiquitination by CM-bound CRL4^CRBN. SENP8 affects the neddylation status of CUL4A and CUL4B, potentially by cleaving detrimental Nedd8 (N8)-conjugates from Nedd8-specific E1 [E1(N8)] and E2 [E2(N8)] enzymes, and thereby affects CRL4^CRBN activity. CRBN overexpression promotes assembly of active CRL4^CRBN complexes, likely by outcompeting other DDB1/DDB1-CUL4–associated factors (DCAF) substrate recognition modules for limiting pools of CUL4A/B. Conversely, increased expression of unneddylated CUL4A/B, either as a consequence of SENP8 inactivation or as a result of expression of nonneddylatable mutants, interferes with CRL4^CRBN activity in a dominant-negative manner, potentially by sequestration of DDB1/CRBN on inactive complexes. Our data and this model suggest that CRBN and CUL4A/B expression can be limiting. CUL4A, CUL4B (together referred to as CUL4A/B), DDB1, UBE2G1, SENP8, RBX1, and CRBN represent gene symbols. CSN, COP9 signalosome.