CUL4A

Cullin-4A is a protein that in humans is encoded by the CUL4A gene.[4][5] CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.

CUL4A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2HYE, 4A0K
Identifiers
Aliases	CUL4A, cullin 4A
External IDs	OMIM: 603137 MGI: 1914487 HomoloGene: 81724 GeneCards: CUL4A
Gene location (Mouse) Chr. Chromosome 8 (mouse)[1] Band 8|8 A1.1 Start 13,105,621 bp[1] End 13,147,940 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity • ubiquitin protein ligase binding • GO:0001948 protein binding Cellular component • nucleoplasm • Cul4-RING E3 ubiquitin ligase complex • cullin-RING ubiquitin ligase complex • Cul4A-RING E3 ubiquitin ligase complex • SCF ubiquitin ligase complex Biological process • ubiquitin-dependent protein catabolic process • negative regulation of granulocyte differentiation • nucleotide-excision repair, DNA damage recognition • negative regulation of cell proliferation • positive regulation of G1/S transition of mitotic cell cycle • intrinsic apoptotic signaling pathway • regulation of protein metabolic process • somatic stem cell population maintenance • nucleotide-excision repair, DNA incision • GO:0022415 viral process • cell cycle arrest • transcription-coupled nucleotide-excision repair • positive regulation of cell proliferation • DNA damage response, detection of DNA damage • cellular response to DNA damage stimulus • regulation of DNA damage checkpoint • global genome nucleotide-excision repair • in utero embryonic development • regulation of nucleotide-excision repair • nucleotide-excision repair, DNA incision, 5'-to lesion • nucleotide-excision repair, preincision complex stabilization • DNA repair • nucleotide-excision repair, preincision complex assembly • post-translational modification • proteasome-mediated ubiquitin-dependent protein catabolic process • protein ubiquitination • G1/S transition of mitotic cell cycle • haematopoiesis • SCF-dependent proteasomal ubiquitin-dependent protein catabolic process • nucleotide-excision repair, DNA duplex unwinding • nucleotide-excision repair, DNA incision, 3'-to lesion Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	8451	99375
Ensembl	n/a	ENSMUSG00000031446
UniProt	Q13619	Q3TCH7
RefSeq (mRNA)	NM_001008895 NM_001278513 NM_001278514 NM_003589	NM_146207 NM_001363448 NM_001363450
RefSeq (protein)	NP_001008895 NP_001265442 NP_001265443 NP_003580 NP_001341867 NP_001341868 NP_001341869 NP_001341870 NP_001341871 NP_001341872 NP_001341873	NP_666319 NP_001350377 NP_001350379
Location (UCSC)	n/a	Chr 8: 13.11 – 13.15 Mb
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Structure

CUL4A protein is 759 amino acids long and forms an extended, rigid structure primarily consisting of alpha-helices. At the N-terminus, CUL4A binds to the beta-propeller of the DDB1 adaptor protein which interacts with numerous DDB1-CUL4-Associated Factors (DCAFs). As a result, the N-terminus is crucial for the recruitment of substrates for the ubiquitin ligase complex. At the C-terminal end, CUL4A interacts with the RBX1/ROC1 protein via its RING domain. RBX1 is a core component of Cullin-RING ubiquitin ligase (CRL) complexes and functions to recruit E2 ubiquitin conjugating enzymes. Therefore, the C-terminus of CUL4A - along with RBX1 and activated E2 enzymes - compose the catalytic core of CRL4 complexes. CUL4A is also modified by covalent attachment of a NEDD8 molecule at a highly conserved lysine residue in the C-terminal region. This modification appears to induce conformational changes which promotes flexibility in the RING domain of cullin proteins and enhanced ubiquitin ligase activity.[6]

Overall, CRL4A complexes have a modular structure which allows for sophisticated regulation by the cell and influence over numerous substrates and processes in the cell. Although the individual parts vary, all cullin-based ubiquitin ligases exhibit these characteristics.[7]

Function

DNA damage and repair

The DDB1 adaptor protein was initially characterized as the large subunit of a heterodimeric complex (UV-DDB) that was found to recognize damaged DNA and participate in a form of repair known as nucleotide excision repair (NER). The smaller subunit of this Damaged DNA Binding protein complex is known as DDB2 and is able to directly bind DNA lesions associated with UV-irradiation. DDB2 is a DCAF protein and is both a ubiquitination substrate of the CRL4 complex and also serves as an E3 ligase protein for other substrates such as XPC and histones (see next section) near the damage site.[8] Due to its ubiquitination of DNA damage-recognizing proteins DDB2 and XPC, CUL4A has been described as a negative regulator of NER activity.[9][10] In addition to the "global" type of NER, the CRL4A complex also appears to play a role in "transcription-coupled" NER in conjunction with the Cockayne Syndrome A protein.[11] CRL4A complexes appear to be activated by certain types of DNA damage (most notably, UV-irradiation) and several substrates are preferentially ubiquitinated after DNA damage induction.

Chromatin remodeling

CUL4A's role in modifying chromatin is largely related to DNA repair activities and occurs after DNA damage induction. Both CUL4A and its closely related homolog CUL4B may ubiquitinate histones H2A, H3 and H4.[12][13] The yeast homolog of CUL4A, Rtt101, ubiquitinates histone H3 and promotes nucleosome assembly and CRL4A complexes perform similar functions in human cells.[14] CRL4 complexes also affect histone methylation events and chromatin structure through regulation of histone methyltransferases.[15] The histone H4 monomethylase PR-Set7/SET8 is ubiquitinated on chromatin by CRL4(Cdt2) complexes during S phase and following DNA damage in a PCNA-dependent manner.[16][17][18]

Regulation of the cell cycle and DNA replication

CRL4A complexes regulate entry into the DNA synthesis phase, or S phase, of the mitotic cycle by regulating protein expression levels of the replication licensing factor protein Cdt1 and cyclin-dependent kinase inhibitor p21. In both cases, CRL4A utilizes Cdt2 as the DCAF to bind both substrates in a PCNA-dependent manner. During unperturbed cell cycle progression, ubiquitination and downregulation of these proteins by CRL4A^Cdt2 occurs at the onset of DNA replication. DNA damage such as UV irradiation also induces CRL4A^Cdt2-mediated destruction of those proteins. Both substrates are also regulated by the SCF^Skp2 complex.

CRL4-mediated destruction of p21 relieves cyclin E-Cdk2 inhibition and promotes S phase entry. Loss of Cdt2 expression increases p21 expression in cells and stabilizes p21 following UV-irradiation.[19] CUL4A deletion results in delayed S phase entry in mouse embryonic fibroblasts, which is rescued by deletion of p21.[10] In human retinal pigment epithelial cells, loss of Cdt2 expression also result in p21 dependent delayed S-phase entry, and re-expression of p21 in S-phase, which results cycles of incomplete replication, long term accumulation of p21, and in some cases induction of apoptosis.[20]

After promoting initiation of eukaryotic DNA replication at the origin, Cdt1 is inactivated by Geminin and targeted for degradation by the SCF^Skp2 and CRL4^Cdt2 complexes. Cdt1 expression is stabilized by RNAi-mediated knockdown of DDB1 or both CUL4A and CUL4B, which suggests redundant or overlapping function of the two CUL4 proteins for Cdt1 regulation.[21][22] Only reduction of Geminin expression seems to induce re-replication in Cdt1-overexpressing cells.

CRL4s also utilize Cdt2 and PCNA to degrade the p12 subunit of DNA polymerase δ during S phase and after UV irradiation.[23]

Haematopoiesis

CRL4A complexes appear to induce the degradation of numerous members of the HOX transcription family, which are essential regulators of haematopoiesis.[24] The first member of the HOX family identified as a target of CRL4A-mediated degradation is HOXA9, which is essential for haematopoietic stem cell maintenance and has been implicated in a subset of myeloid leukemias.[25][26] The HOXA9 degron lies within the homeodomain, which is crucial for DNA binding. Sequence alignment studies showed that there is a highly conserved "LEXE" motif within helix one of the homeodomain. When multiple amino acids within this motif were mutated, HOXB4 became resistant to CRL4A-mediated degradation.[24] The substrate receptor, or DCAF, required for HOX protein degradation remains unknown.

Spermatogenesis and meiosis

The Cul4a gene is required for normal spermatogenesis and meiosis in male germ cells of mice.[27][28] Cul4a^−/− males produce abnormal sperm and are infertile. While both CUL4A and CUL4B are expressed in male gametes, CUL4A is highly expressed in pachytenes and diplotenes. It is at these stages that CUL4A-deficient male germ cells exhibit high levels of apoptosis, improper DNA repair and accumulation of the CRL4 substrate Cdt1.

Dysregulation

Cancer

The chromosomal region ch13q34 which contains the CUL4A gene is amplified in 3-6% of certain carcinomas including: breast, uterine, lung, stomach and colorectal cancers.[29] CUL4A is also mutated or amplified in about 4% of melanomas (although the mutations are dispersed and individual mutations occur sporadically).

In mouse models, Cul4a knockout resulted in pronounced resistance to UV-induced skin carcinogenesis.[10] Cre-induced Cul4a overexpression in mouse lung tissue promoted hyperplasia.[30]

Due to the observed amplification of CUL4A in several carcinomas and the fact that CRL4 complexes target multiple DNA repair and tumor suppressor genes, CUL4A can be considered an oncogene in certain contexts.

Viral pathogenesis

Due to its robust expression (particularly during DNA replication) and modular nature, CRL4A complexes can be co-opted or "hijacked" to promote viral proliferation in mammalian cells.

Certain paramyxoviruses avoid the interferon response in cells by targeting STAT1 and disrupting signaling. Simian virus 5 and type II human parainfluenza virus express a protein, named "V", which acts as a substrate receptor and bridges an interaction between DDB1 and STAT proteins (the structure of the CRL4A^SV5V complex is pictured in the inset) - thus inducing STAT1 ubiquitination and degradation[31][32]

DCAF1 is also named VPRBP due to its interaction with HIV-1 protein Vpr. Although DCAF1/VPRBP appears to have a crucial function in tumor suppression, DNA replication and embryonic development, HIV-1 "hijacks" the ubiquitin ligase complex to induce arrest of the cell cycle in G2 phase.[33][34][35] The CRL4A^DCAF1-Vpr induces ubiquitination of the nuclear isoform of uracil-DNA glycosylase.[36][37] HIV-2 also appears to utilize CRL4A^DCAF1 via Vpx protein-induced destruction of a lentivirus-inhibiting deoxynucleoside triphosphohydrolase named SAMHD1.[38][39]

Thalidomide treatment

In 2010, Ito et al. reported that Cereblon, a DCAF protein, was a major target of the teratogenic compound thalidomide.[40] 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.[41][42]

Interactions and substrates

Human CUL4A forms direct interactions with:

• DDB1[43]
• RBX1[44][45]
• CAND1[46]
• The COP9 signalosome[47]

Human CUL4A-DDB1-RBX1 complexes promote the ubiquitination of:

• DDB2[48]
• XPC[8][10]
• p21[19][49]
• CDT1[21][22]
• p12 subunit of DNA Pol δ[23]
• HOXA9[25]
• HOXB4[24]
• PR-Set7/SET8[16][17][18]
• STAT1^†[31][32]
• UNG2^†[36][37]
• SAMHD1^†[38][39]
• IKZF1^§[41][42]
• IKZF3^§[41][42]

^†protein is a CRL4A substrate only when directed by viral proteins
^§protein is a CRL4A substrate only when directed by IMiDs

Notes

References

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External links

• Human CUL4A genome location and CUL4A gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: Q13619 (Cullin-4A) at the PDBe-KB.

Further reading

• Osaka F, Kawasaki H, Aida N, Saeki M, Chiba T, Kawashima S, Tanaka K, Kato S (Aug 1998). "A new NEDD8-ligating system for cullin-4A". Genes & Development. 12 (15): 2263–8. doi:10.1101/gad.12.15.2263. PMC 317039. PMID 9694792.
• Chen LC, Manjeshwar S, Lu Y, Moore D, Ljung BM, Kuo WL, Dairkee SH, Wernick M, Collins C, Smith HS (Aug 1998). "The human homologue for the Caenorhabditis elegans cul-4 gene is amplified and overexpressed in primary breast cancers". Cancer Research. 58 (16): 3677–83. PMID 9721878.
• Ohta T, Michel JJ, Schottelius AJ, Xiong Y (Apr 1999). "ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity". Molecular Cell. 3 (4): 535–41. doi:10.1016/S1097-2765(00)80482-7. PMID 10230407.
• Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S, Tanaka K (Nov 1999). "Covalent modification of all members of human cullin family proteins by NEDD8". Oncogene. 18 (48): 6829–34. doi:10.1038/sj.onc.1203093. PMID 10597293.
• Lyapina S, Cope G, Shevchenko A, Serino G, Tsuge T, Zhou C, Wolf DA, Wei N, Shevchenko A, Deshaies RJ (May 2001). "Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome". Science. 292 (5520): 1382–5. doi:10.1126/science.1059780. PMID 11337588. S2CID 14224920.
• Chen X, Zhang Y, Douglas L, Zhou P (Dec 2001). "UV-damaged DNA-binding proteins are targets of CUL-4A-mediated ubiquitination and degradation". The Journal of Biological Chemistry. 276 (51): 48175–82. doi:10.1074/jbc.M106808200. PMID 11673459.
• Yasui K, Arii S, Zhao C, Imoto I, Ueda M, Nagai H, Emi M, Inazawa J (Jun 2002). "TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas". Hepatology. 35 (6): 1476–84. doi:10.1053/jhep.2002.33683. PMID 12029633.
• Liu J, Furukawa M, Matsumoto T, Xiong Y (Dec 2002). "NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases". Molecular Cell. 10 (6): 1511–8. doi:10.1016/S1097-2765(02)00783-9. PMID 12504025.
• Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (May 2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". The Journal of Biological Chemistry. 278 (18): 15905–10. doi:10.1074/jbc.M213070200. PMID 12609982.
• Groisman R, Polanowska J, Kuraoka I, Sawada J, Saijo M, Drapkin R, Kisselev AF, Tanaka K, Nakatani Y (May 2003). "The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage". Cell. 113 (3): 357–67. doi:10.1016/S0092-8674(03)00316-7. PMID 12732143.
• Higa LA, Mihaylov IS, Banks DP, Zheng J, Zhang H (Nov 2003). "Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint". Nature Cell Biology. 5 (11): 1008–15. doi:10.1038/ncb1061. PMID 14578910.
• Wertz IE, O'Rourke KM, Zhang Z, Dornan D, Arnott D, Deshaies RJ, Dixit VM (Feb 2004). "Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase" (PDF). Science. 303 (5662): 1371–4. doi:10.1126/science.1093549. PMID 14739464.
• Obuse C, Yang H, Nozaki N, Goto S, Okazaki T, Yoda K (Feb 2004). "Proteomics analysis of the centromere complex from HeLa interphase cells: UV-damaged DNA binding protein 1 (DDB-1) is a component of the CEN-complex, while BMI-1 is transiently co-localized with the centromeric region in interphase". Genes to Cells. 9 (2): 105–20. doi:10.1111/j.1365-2443.2004.00705.x. PMID 15009096.
• Hu J, McCall CM, Ohta T, Xiong Y (Oct 2004). "Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage". Nature Cell Biology. 6 (10): 1003–9. doi:10.1038/ncb1172. PMID 15448697.
• Nag A, Bagchi S, Raychaudhuri P (Nov 2004). "Cul4A physically associates with MDM2 and participates in the proteolysis of p53". Cancer Research. 64 (22): 8152–5. doi:10.1158/0008-5472.CAN-04-2598. PMID 15548678.
• Matsuda N, Azuma K, Saijo M, Iemura S, Hioki Y, Natsume T, Chiba T, Tanaka K, Tanaka K (May 2005). "DDB2, the xeroderma pigmentosum group E gene product, is directly ubiquitylated by Cullin 4A-based ubiquitin ligase complex". DNA Repair. 4 (5): 537–45. doi:10.1016/j.dnarep.2004.12.012. PMID 15811626.