The E3 ubiquitin ligase HUWE1/Mule/ARF-BP1 plays an important role in diverse biological processes including DNA damage repair and apoptosis. Our previous study has shown that in response to DNA damage HUWE1 was downregulated in CUL4B-mediated ubiquitination and subsequent proteasomal degradation, and CUL4B-mediated regulation of HUWE1 was important for cell survival upon DNA damage. CUL4B is a core component of the CUL4B Ring ligase complexes containing ROC1, DDB1 and a DDB1-Cullin Associated Factors (DCAFs), the latter of which are DDB1-binding WD40 adaptors critical for substrate recognition and recruitment. However, the identity of DCAF in CRL4B that mediates degradation of HUWE1 remains elusive. Here we report that RBBP7 is the DCAF in the CRL4B complex bridging the DDB1-CUL4B-ROC1 to HUWE1. Loading of HUWE1 to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome mediated degradation. Overexpression of RBBP7 promoted HUWE1 protein degradation, while depletion of RBBP7 stabilized HUWE1, and hence accelerated the degradation of MCL-1 and BRCA1, two substrates of HUWE1 that are critical in apoptosis and DNA damage repair. Taken together, these data reveal CRL4B^RBBP7 is the E3 ligase responsible for the proteasomal degradation of HUWE1, and further provide a potential strategy for cancer therapy by targeting HUWE1 and the CUL4B E3 ligase complex.