CUL4B

CUL4B-based E3 ubiquitin ligase complexes often demonstrate overlapping activity with CUL4A-based complexes. Both CRL4 complexes utilize Cdt2 and the DNA processivity factor PCNA to induce the ubiquitination and degradation of replication licensing factor Cdt1 and cyclin-dependent kinase inhibitor p21 in a proteasome-dependent manner.[9][10] CRL4^Cdt2 also degrades PCNA-bound PR-Set7/SET8, which is a histone 4 methyltransferase, and the p12 subunit of DNA polymerase δ, which is crucial for DNA replication.[11][12] As a result, CRL4 complexes are able to control the onset of DNA replication, chromatin remodeling and progression through the cell cycle.

Loss of Cul4b in mice causes embryonic lethality and defects in placental development. The extra-embryonic tissue of these developing mice also showed increased rates of apoptosis and a decrease in cell proliferation. When Cul4b deletion was limited to the epiblast (only in Sox2-expressing tissue), it was possible to generate living mice.[13]

Mice that do not express CUL4B in epiblast tissue demonstrate normal brain morphology but decrease number of parvalbumin (PV)-positive GABAergic interneurons - particularly in the dentate gyrus.[14] In these mice, certain dendritic features of hippocampal neurons were also affected by Cul4b loss, which may explain the observed increases in epileptic susceptibility and spatial learning defects. These phenotypes resembled features seen in patients with X-linked intellectual disability (see below).

Loss-of-function CUL4B mutation events have been discovered in numerous patients with X-linked intellectual disability, which is characterized by aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus and tremor.[15][16][17] CUL4B mutations have also been associated with malformations of cortical development.[18]

After HIV infects a cell, the virus "hijacks" either the CUL4B-DDB1 complex or the CUL4A-DDB1 complex via the same mechanism. Essentially, HIV proteins such as Vpr and Vpx bind to VPRBP (a DDB1-binding substrate receptor protein) and induce the ubiquitination and degradation of SAMHD1 and UNG2 to promote viral replication.[19] These proteins are not degraded by CRL4 complexes in the absence of virus.

According to data from The Cancer Genome Atlas, CUL4B is mutated in 21% of pancreatic carcinomas with a recurring truncating mutation at amino acid 143. CUL4B is also mutated or amplified in 3-5% of lung cancers. The significance of these observed mutations has not been determined.

In 2010, Ito et al. reported that Cereblon, a DCAF protein, was a major target of the teratogenic compound thalidomide.[20] Thalidomide and other derivatives such as pomalidomide and lenalidomide are known as immunomodulatory drugs (or IMiDs) and have been investigated as therapeutic agents for autoimmune diseases and several cancers - particularly myelomas. Recent reports show that IMiDs bind to CRL4^CRBN and promote the degradation of IKZN1 and IKZN3 transcription factors, which are not normally targeted by CRL4 complexes.[21][22]