Table 3.
Major mammalian substrates of CRL4 and their biological impacts
| Substrate recognition protein | Scaffold | Substrate | Modification | Biological impact |
|---|---|---|---|---|
| DCAF1 | CUL4A | LATS1 | Degradation | Oncogenic contribution139,140 |
| CUL4A | LATS2 | Altered activity | Oncogenic contribution139 | |
| CUL4A | HLTF | Degradation | Triggering HIV replication110 | |
| CUL4A | Dicer1 | Degradation | Enhanced HIV infection258; Colon cancer progression109 | |
| CUL4A/B | FOXM1 | Degradation | Cell cycle arrest136 | |
| CUL4A/B | PP2A | Degradation | Crucial for oocyte meiosis and female fertility67 | |
| CUL4A/B | MyoD | Degradation | Halted differentiation of skeletal muscle137 | |
| CUL4A | MCM10 | Degradation | Cell cycle arrest259,260 | |
| CUL4B | TR4 | Degradation | Resistant to high fat caused fatty liver261 | |
| CUL4A/B | SAMHD1 | Degradation | Facilitating HIV replication262 | |
| CUL4A/B | TET1/2/3 | Altered activity | Essential for ovary maturity69; Tumor263 suppression |
|
| CUL4A/B | RORα | Degradation | Transcriptional repression138 | |
| CUL4A | UNG2 | Degradation | Cell cycle arrest264,265 | |
| CUL4A | SMUG1 | Degradation | Cell cycle arrest264 | |
| CUL4A | NF2 | Degradation | Activation of oncogenic pathways141 | |
| DCAF2 | CUL4A | CRY1 | Degradation | Promotion of liver gluconeogenesis; Homeostasis of molecular circadian behavior72,147 |
| CUL4A/B | CDT1 | Degradation | Stimulating the proliferation of melanoma150,152 | |
| CUL4A/B | p21 | Degradation | Stimulating the proliferation of melanoma150; Regulation of replication licensing98 | |
| CUL4A | p53 | Degradation | Cell cycle control266 | |
| CUL4A/B | SET7 | Degradation | Maintaining genomic integrity143–145 | |
| CUL4A/B | SET8 | Degradation | Stimulating the proliferation of melanoma150; DNA damage control145,267 | |
| CUL4A/B | PCNA | Altered activity | Enhanced translesion DNA synthesis268 | |
| CUL4A/B | p12 | Degradation | DNA repair control269 | |
| CUL4A | CHK1 | Degradation | Cell cycle progression146 | |
| CUL4A/B | MMSET | Degradation | Cell cycle arrest270 | |
| CUL4A/B | XPG | Degradation | DNA repair271 | |
| CUL4A/B | TDG | Degradation | Homeostasis of DNA replication272 | |
| CUL4A | SDE2 | Degradation | Protection of genomic stability against replication stresses273 | |
| CUL4A/B | CDC6 | Degradation | Cell cycle regulation274 | |
| CUL4A | Tob | Degradation | Apoptotic response to DNA damage275 | |
| CUL4A | GCN5 | Degradation | Transcriptional suppression148 | |
| DCAF4L2 | CUL4A | PPM1B | Degradation | Increased invasion of colorectal cancer276 |
| DCAF7 | CUL4A/B | LigI | Degradation | NS277 |
| DCAF8 | CUL4A | H3 | Altered activity | Postnatal liver maturation278 |
| CUL4B | CDC25A | Degradation | NS170 | |
| DCAF9 | CUL4A/B | H2A | Altered activity | Suppressed adipogenesis279 |
| DCAF11 | CUL4A | NRF2 | Degradation | More sensitive to chemotherapies171 |
| CUL4A | SLBP | Degradation | Cell cycle homeostasis280,281 | |
| CUL4B | p21 | Degradation | Inhibiting cell cycle progression172 | |
| DCAF15 | CUL4A/B | CAPERα | Degradation | Anti-growth effect in cancer cells173 |
| AhR | CUL4B | ERα | Degradation | NS282 |
| COP1 | CUL4A | ETV5 | Degradation | Lung homeostasis and tumor suppression166 |
| CUL4A | c-Jun | Degradation | Inhibition on oncogenic transcriptions167 | |
| COPS8 | CUL4A | CENP-A | Subcellular relocalization | Homeostasis of mitosis283 |
| CRBN | CUL4A/B | IKZF1/3 | Degradation | Anti-tumor impacts against multiple myeloma cells162 |
| CUL4A | ZFP91 | Degradation | NS284 | |
| CUL4A | GSPT1 | Degradation | Anti-tumor impacts against leukemic cells163 | |
| CUL4A/B | APP | Degradation | Alleviation of neurodegeneration159 | |
| CUL4A | GS | Degradation | NS185 | |
| CUL4A/B | CK1α | Degradation | Inhibition on myelodysplastic syndrome164 | |
| CUL4A/B | CLC-1 | Degradation | Homeostasis of membrane excitability160 | |
| CUL4A | SLO1 | Altered activity | Preventing epileptogenesis71 | |
| DDB2 | CUL4A | p27 | Degradation | Cell cycle progression156 |
| CUL4A | AR | Degradation | Suppression of prostate cancer proliferation154,285 | |
| CUL4A/B | H2A | Altered activity | DNA repair84 | |
| CUL4A/B | HBO1 | Degradation | Suppressed cell proliferation158 | |
| CUL4A | DDB2 | Degradation | Regulation of DNA damage286,287 | |
| FBXO44 | CUL4B | RGS2 | Degradation | NS288 |
| FBXW5 | CUL4A | DLC1 | Degradation | Growth of lung cancer cells289 |
| CUL4A/B | TSC2 | Degradation | Homeostasis of cell growth290 | |
| GNB2 | CUL4A | GRK2 | Degradation | Cardiovascular protection249 |
| GNB3 | CUL4A | GRK2 | Degradation | Cardiovascular homeostasis85 |
| HBx | CUL4A/B | SMC5/6 | Degradation | Increased replication of HBV128 |
| HOXB4 | CUL4A | Geminin | Degradation | Elevated proliferation of hematopoietic stem and progenitor cells291 |
| RBBP7 | CUL4A/B | CENP-A | Subcellular relocalization | Homeostasis of mitosis292 |
| STRAP | CUL4A | PNKP | Degradation | Susceptible to oxidative DNA damage293 |
| WDR70 | CUL4A/B | H2B | Altered activity | Stability of cell division294 |
| Other substrates* | CUL4A/B | γ-tubulin | Degradation | Stability of centrosome295 |
| CUL4B | HUWE1 | Degradation | Reduced apoptosis after DNA damage296 | |
| CUL4A/B | AMBRA1 | Degradation | Autophagy termination297 | |
| CUL4B | p53 | Degradation | Impeding stress-induced cellular senescence298 | |
| CUL4A | PEX7P | Degradation | Control of peroxisome biogenesis299 | |
| CUL4A | HOXB4 | Degradation | Decreased proliferation of hematopoietic stem cells60 | |
| CUL4B | CSN5 | Degradation | Regulation of bone morphogenetic signaling300 | |
| CUL4A | p73 | Altered activity | Transcriptional repression301 | |
| CUL4A | GRK5 | Degradation | NS302 | |
| CUL4A | ORCA | Degradation | Cell cycle regulation303 | |
| CUL4B | WDR5 | Degradation | Promoting neurite outgrowth79 | |
| CUL4B | Peroxiredoxin III | Degradation | Increased production of cellular reactive oxygen species304 | |
| CUL4A | RASSF1A | Degradation | Cell cycle progression305 | |
| CUL4B | cyclin E | Degradation | Cell cycle progression306 | |
| CUL4A | CHK1 | Degradation | Genomic instability307 | |
| CUL4B | H3/H4 | Altered activity | Facilitating cellular response to DNA damage308 | |
| CUL4A | p27 | Degradation | Cell proliferation50 | |
| CUL4A | HOXA9 | Degradation | Myelocytic maturation49 | |
| CUL4A | REDD1 | Degradation | Activation of mTOR signaling309 |
Those proteins are assumed to be the substrates of CRL4 without detailed description of binding motif and interactions with substrate recognition proteins.
Abbreviations:COPS8: COP9 signalosome subunit 8; CENP-A: centromere protein A; DCAF2: alias CDT2; CRY1: cryptochrome 1; TR4: nuclear receptor subfamily 2 group C member 2 (alias NR2C2); CRBN: cereblon; ZFP91: zinc finger protein 91; NS: not specified; DCAF11: alias WDR23; CAPERα: coactivator of activating protein-1 and estrogen receptor α; NRF2: nuclear factor erythroid 2 like 2; LATS1: large tumor suppressor 1; FOXM1: forkhead box M1; ETV5: ETS variant 5; AR: androgen receptor; H3: histone H3 protein; ERα: estrogen receptor α; SDE2: SDE2 telomere maintenance homolog; HBx: hepatitis B virus regulatory protein X; SMC5: structural maintenance of chromosome 5; LigI: DNA ligase I; GNB3: G protein subunit beta 3; GRK2: G protein-coupled receptor kinase 2; GSPT1: G1 to S phase transition 1; CDT1: chromatin licensing and DNA replication factor 1; SET8: lysine methyltransferase 5A (alias KMT5A); APP: amyloid precursor protein; SLBP: stem-loop binding protein; PPM1B: protein phosphatase, Mg2+/Mn2+ dependent 1B; WDR70: WD repeat domain 70; GS: glutamine synthetase; HLTF: helicase-like transcription factor; MMSET: nuclear receptor binding SET domain protein 2 (alias NSD2); HBO1: lysine acetyltransferase 7 (alias KAT7); PP2A: phosphatase 2A; CK1α: casein kinase 1A1; MCM10: minichromosome maintenance 10 replication initiation factor; CLC-1: chloride voltage-gated channel 1; FBXO44: F-box protein 44; RGS2: regulator of G protein signaling 2; TET: tet methylcytosine dioxygenase; XPG: Xeroderma pigmentosum group G protein; TDG: thymine DNA glycosylase; SLO1: potassium calcium-activated channel subfamily M alpha 1 (alias KCNMA1); CDC6: cell division cycle 6; FBXW5: F-box and WD repeat domain containing 5; DLC1: DLC1 Rho GTPase activating protein; CHK1: checkpoint kinase 1; RORα: RAR related orphan receptor A; STRAP: serine-threonine kinase receptor associated protein; PNKP: polynucleotide kinase 3’-phosphatase; UNG2: uracil DNA glycosylase 2; SMUG1: single-strand-selective monofunctional uracil-DNA glycosylase 1; GCN5: lysine acetyltransferase 2A (alias KAT2A); PCNA: proliferating cell nuclear antigen; β-TRCP: beta-transducin repeat containing E3 ubiquitin protein ligase; REDD1: regulated in development and DNA damage responses 1; TSC2: TSC complex subunit 2; NF2: neurofibromin 2; AhR: aryl hydrocarbon receptor; ERα: estrogen receptor α; COP1: ring finger and WD repeat domain 2 (RFWD2); CDC25A: cell division cycle 25A; HUWE1: HECT, UBA and WWE domain containing 1; AMBRA1: autophagy and beclin 1 regulator 1; PEX7P: peroxisomal biogenesis factor 7p; HOXB4: homeobox B4; CSN5: COP9 signalosome subunit 5; ORCA: origin recognition complex subunit 1; RASSF1A: RAS association domain family 1 isoform A; CHK1: checkpoint kinase 1; SKP2: S-phase kinase associated protein 2; HOXA9: homeobox A9; SAMHD1: SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1.