| CUL4B is a cullin family scaffold protein that forms the core of CUL4B‑RING E3 ubiquitin ligase complexes and organizes modular CRL4B assemblies that catalyze polyubiquitination and proteasomal degradation of defined sets of cell‑cycle, chromatin, and signaling regulators. The protein shares high sequence similarity with CUL4A but contains an extended N‑terminal region that includes a nuclear localization signal and supports predominant nuclear localization, and its C‑terminal cullin domain binds the RING finger protein RBX1, while the adaptor DDB1 bridges CUL4B to a variable set of DCAF substrate receptors that confer target specificity. CRL4B complexes use DCAF adaptors such as Cdt2, AMBRA1, DDB2, TRPC4AP, and DCAF12 to recognize substrates including CDT1, cyclin E, cyclin D isoforms, p21, histones H2A, H3, and H4, and specific mitochondrial or signaling proteins, and CUL4B acts as a rigid scaffold that positions bound substrates and the E2–ubiquitin conjugate to promote Lys48‑linked polyubiquitination and subsequent proteasomal degradation. Nuclear CRL4B–DDB1–DDB2 complexes are targeted to UV‑damaged chromatin and monoubiquitinate histone H2A and other chromatin components at sites of DNA damage, functions that contribute to nucleotide excision repair, replication licensing control through CDT1 turnover, and maintenance of genome stability. CUL4B also regulates the mammalian target of rapamycin complex 1 (mTORC1) pathway through interaction with the mTOR component MLST8 and proteasome‑dependent ubiquitination events, linking CRL4B activity to control of cell growth, size, and metabolism. In G1–S progression, the DCX(AMBRA1) CRL4B complex ubiquitinates phosphorylated cyclin‑D family proteins and Elongin C from CRL5 complexes, and CUL4B participates with CUL4A in ubiquitination of cyclin E, thereby shaping cyclin–CDK activity profiles and enforcing proper G1 duration and S‑phase entry. CRL4B complexes that incorporate TRPC4AP or DCAF12 act in the DesCEND pathway and recognize C‑terminal degrons in substrates to trigger their degradation, extending CUL4B function into C‑end quality control and turnover of specific regulatory proteins. In immune cells, CUL4B‑RING E3 ligases regulate differentiation and effector functions of CD4⁺ T cells and other subsets by controlling the stability of transcription factors and signaling intermediates, and CRL4B activity aligns with regulation of cytokine production, Toll‑like receptor signaling, and maintenance of immune homeostasis. Oncogenic roles of CUL4B include overexpression and amplification in colorectal, bladder, breast, and other cancers, where CRL4B complexes promote cell proliferation, invasion, and epithelial–mesenchymal transition through multiple mechanisms that involve inactivation of p53 signaling, activation of Wnt/β‑catenin pathways, and cooperation with histone deacetylase‑containing corepressor complexes. In colorectal cancer, CUL4B acts as a negative regulator of p53 by interacting with MDM2, decreasing p53 half‑life, and reducing levels of p53 downstream targets such as p21 and PUMA, which supports tumor cell proliferation, invasion, and progression. In breast cancer, CRL4B binds MTA1/NuRD, SIN3A, CoREST, and NCoR/SMRT complexes, co‑occupies E‑cadherin and AXIN2 promoters, and coordinates with transcription factors such as Snail and ZEB2 to repress epithelial genes, enhance EMT signaling under hypoxia, and promote cancer stem‑cell–like properties; HIF‑1α directly activates, and ERα–GATA3 represses, CUL4B transcription, placing CUL4B under control of hypoxia and hormone pathways during tumor progression. Across developmental, immune, and oncogenic contexts, CUL4B functions as a nuclear cullin scaffold that assembles DDB1‑ and DCAF‑based CRL4B E3 ligases to couple substrate‑specific ubiquitination of DNA replication factors, cyclins, histones, signaling proteins, and transcriptional repressors with cell‑cycle control, chromatin remodeling, DNA repair, mTOR signaling, immune differentiation, and tumorigenesis. |
