CRL4B interacts with and coordinates the SIN3A-HDAC complex to repress CDKN1A and drive cell cycle progression.

CUL4B, a scaffold protein that assembles CRL4B ubiquitin ligase complex, participates in the regulation of a broad spectrum of biological processes. We here demonstrated a critical role of CUL4B in driving cell cycle progression. We showed that loss of CUL4B resulted in a significantly reduced cell proliferation and G1 cell cycle arrest that were accompanied by the upregulation of the CDK inhibitors p21 and p57. Strikingly, CUL4B was found to negatively regulate the function of p21 via transcription repression, but not via proteolysis. Furthermore, we demonstrated that CRL4B and SIN3A/HDAC complexes interact with each other and co-occupy the CDKN1A and CDKN1C promoters. Lack of CUL4B led to a decreased retention of SIN3A/HDAC components and increased levels of acetylated H3 and H4. Interestingly, the ubiquitination function of CRL4B is not required for the stable retention of SIN3A/HDAC on the promoters of target genes. Thus, in addition to directly contributing to epigenetic silencing by catalyzing H2AK119 monoubiquitination, CRL4B also facilitates the deacetylation function of SIN3A/HDAC. Our findings reveal a coordinated action between CRL4B and SIN3A/HDAC complexes in transcription repression.