CUL3 and cancer: SPOP plays a potential role in tumorigenicity because it is a frequently mutated gene in primary cancer.39–45 SPOP is a member of the MATH–BTB protein family, containing an N-terminal meprin and TRAF homology (MATH) domain (responsible for substrate recognition and interaction) and a C-terminal BTB domain (binds CUL3 and forms the functional E3 ubiquitin ligase complex) (Supplementary information, Fig. S7a).46 BTB domain-deleted SPOP lost its effect on mediating ILF3 poly-ubiquitination (Supplementary information, Fig. S7b).