Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

Abstract

The cullin 4 subfamily of genes includes CUL4A and CUL4B, which share a mostly identical amino acid sequence aside from the elongated N-terminal region in CUL4B. Both act as scaffolding proteins for modular cullin RING ligase 4 (CRL4) complexes which promote the ubiquitination of a variety of substrates. CRL4 function is vital to cells as loss of both genes or their shared substrate adaptor protein DDB1 halts proliferation and eventually leads to cell death. Due to their high structural similarity, CUL4A and CUL4B share a substantial overlap in function. However, in some cases, differences in subcellular localization, spatiotemporal expression patterns and stress-inducibility preclude functional compensation. In this review, we highlight the most essential functions of the CUL4 genes in: DNA repair and replication, chromatin-remodeling, cell cycle regulation, embryogenesis, hematopoiesis and spermatogenesis. CUL4 genes are also clinically relevant as dysregulation can contribute to the onset of cancer and CRL4 complexes are often hijacked by certain viruses to promote viral replication and survival. Also, mutations in CUL4B have been implicated in a subset of patients suffering from syndromic X-linked intellectual disability (AKA mental retardation). Interestingly, the antitumor effects of immunomodulatory drugs are caused by their binding to the CRL4CRBN complex and re-directing the E3 ligase towards the Ikaros transcription factors IKZF1 and IKZF3. Because of their influence over key cellular functions and relevance to human disease, CRL4s are considered promising targets for therapeutic intervention.

Selective degradation of splicing factor CAPERα by anticancer sulfonamides

“…Interestingly, the double knockdown of CUL4A and CUL4B prevented E7820-induced CAPERα degradation to a significant degree, whereas the single knockdown of either CUL4A or CUL4B did not ( Supplementary Fig. 7), indicating that CUL4A and CUL4B may be involved in DCAF15-DDB1-mediated protein ubiquitination in a redundant manner 14,30 .…”

“…2b, Supplementary Data Set 2). DDB1 functions as a linker between the CUL4 scaffolds and DCAF substrate receptors to build the CRL4 complexes, which regulate diverse protein ubiquitination and cellular functions 13,14 . To confirm whether DCAF15-DDB1 plays a key role in CAPERα degradation, we performed an siRNAmediated knockdown of DCAF15 and DDB1 in HCT116 cells.…”

“…1) was reported to target cereblon (CRBN), a DDB1-and CUL4-associated factor (DCAF), and induce selective degradation of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) and casein kinase 1α (CK1α) as key mechanisms of anticancer activity in multiple myeloma cells and in the deletion 5q (del (5q)) subtype of myelodysplastic syndrome (MDS) [4][5][6][7][8][9][10][11] . CRBN and other DCAFs are components of the CUL4-RING ubiquitin ligase (CRL4) complex and play a central role in substrate recognition for ubiquitination [12][13][14] . Furthermore, recent reports show that conjugation of the phthalimide moiety of thalidomide with a competitive antagonist of BET bromodomains induces degradation of the transcriptional coactivator BRD4 via CRL4 CRBN , suggesting that CRBN-based target-protein degradation may also be applicable to substrate proteins other than IKZF1 and IKZF3, and thus could provide an accessible therapeutic strategy using chemical conjugation techniques [15][16][17][18][19] .…”

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

“…The CRL4 Cdt2 ubiquitin ligase plays a critical role in the prevention of re-replication, as the "master coordinator of cell cycle progression and genome stability" [103]. CRL4 Cdt2 is a member of the Cullin Ring Ligase family of E3 ubiquitin ligases and targets the licensing factors that are involved in the assembly of the pre-replicative complex during G1, so that they are removed during the G1/S transition [104]. The primary targets of CRL4 Cdt2 are Cdt1, p21 (p21 Waf1/CIP1 ) and the histone acetylase Set8.…”

E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking

“…The UPS targets proteins for proteolysis through the conjugation of ubiquitin to substrates, and polyubiquitin tags are formed when additional ubiquitins are attached to the first ubiquitin molecule at specific lysine residues, with lysine 48 (K48) link-age believed to provide maximal signal to be recognized and degraded by the 26S proteasome complex (6,10,11). E3 ubiquitin ligases (E3s) coordinate ubiquitin conjugation (6,10,11) and have garnered significant therapeutic interest in a variety of psychiatric disorders (12–14). Dynamic changes in UPS activity have been reported following exposure to cocaine (15,16); however, virtually nothing is known about the role of E3s in cocaine use disorder.…”