CUL4A

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Cullin 4A
CUL4A-brown-2HYE.png
PDB rendering of CUL4A (brown) based on 2HYE.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol CUL4A
External IDs OMIM603137 MGI1914487 HomoloGene81724 GeneCards: CUL4A Gene
RNA expression pattern
PBB GE CUL4A 201424 s at tn.png
PBB GE CUL4A 201423 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 8451 99375
Ensembl ENSG00000139842 ENSMUSG00000031446
UniProt Q13619 Q3TCH7
RefSeq (mRNA) NM_001008895 NM_146207
RefSeq (protein) NP_001008895 NP_666319
Location (UCSC) Chr 13:
113.86 – 113.92 Mb
Chr 8:
13.11 – 13.15 Mb
PubMed search [3] [4]

Cullin-4A is a protein that in humans is encoded by the CUL4A gene.[1][2] 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.

Structure[edit]

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.[3]

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.[4]

Function[edit]

DNA damage and repair[edit]

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.[5] Due to its ubiquitination of DNA damage-recognizing proteins DDB2 and XPC, CUL4A has been described as a negative regulator of NER activity.[6][7] 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.[8] 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[edit]

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.[9][10] The yeast homolog of CUL4A, Rtt101, ubiquitinates histone H3 and promotes nucleosome assembly and CRL4A complexes perform similar functions in human cells.[11] CRL4 complexes also affect histone methylation events and chromatin structure through regulation of histone methyltransferases.[12] 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.[13][14][15]

Regulation of the cell cycle and DNA replication[edit]

CRL4A complexes regulate entry into the DNA synthesis phase, or S phase, of the mitotic cycle by regulating protein expression levels of the replication licencing 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 CRL4ACdt2 occurs at the onset of DNA replication. DNA damage such as UV irradiation also induces CRL4ACdt2-mediated destruction of those proteins. Interestingly, both substrates are also regulated by the SCFSkp2 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.[16] CUL4A deletion results in delayed S phase entry in mouse embryonic fibroblasts, which is rescued by deletion of p21.[7]

After promoting initiation of eukaryotic DNA replication at the origin, Cdt1 is inactivated by Geminin and targeted for degradation by the SCFSkp2 and CRL4Cdt2 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.[17][18] Only reduction of Geminin expression seems to induce re-replication in Cdt1-overexpressing cells.

Haematopoiesis[edit]

CRL4A complexes appear to induce the degradation of numerous members of the HOX transcription family, which are essential regulators of haematopoiesis.[19] 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.[20][21] 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.[19] The substrate receptor, or DCAF, required for HOX protein degradation remains unknown.

Spermatogenesis and meiosis[edit]

The Cul4a gene is required for normal spermatogenesis and meiosis in male germ cells of mice.[22][23] 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[edit]

Cancer[edit]

CUL4A is amplified in 3-6% of certain carcinomas including: breast, uterine, lung, stomach and colorectal cancers.[24] 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.[7] Cre-induced Cul4a overexpression in mouse lung tissue promoted hyperplasia.[25]

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[edit]

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 protein V acts as a substrate receptor and bridges an interaction between DDB1 and STAT proteins (the structure of the CRL4ASV5V complex is pictured in the inset) - thus inducing STAT1 ubiquitination and degradation[26][27]

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.[28][29][30] The CRL4ADCAF1-Vpr induces ubiquitination of the nuclear isoform of uracil-DNA glycosylase.[31][32] HIV-2 also appears to utilize CRL4ADCAF1 via Vpx protein-induced destruction of a lentivirus-inhibiting deoxynucleoside triphosphohydrolase named SAMHD1.[33][34]

Interactions and substrates[edit]

Human CUL4A forms direct interactions with:

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

protein is a CRL4A substrate only when directed by viral proteins

References[edit]

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  2. ^ "Entrez Gene: CUL4A Cullin 4A". 
  3. ^ Duda D, Borg L, Scott D, Hunt H, Hammel M, Schulman B (Sep 2008). "Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation". Cell 134 (6): 995–1006. doi:10.1016/j.cell.2008.07.022. PMC 2628631. PMID 18805092. 
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  5. ^ a b Sugasawa K, Okuda Y, Saijo M, Nishi R, Matsuda N, Chu G et al. (May 2005). "UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex". Cell 121 (3): 387–400. doi:10.1016/j.cell.2005.02.035. PMID 15882621. 
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  14. ^ a b Tardat M, Brustel J, Kirsh O, Lefevbre C, Callanan M, Sardet C et al. (Nov 2010). "The histone H4 Lys 20 methyltransferase PR-Set7 regulates replication origins in mammalian cells". Nature Cell Biology 12 (11): 1086–93. doi:10.1038/ncb2113. PMID 20953199. 
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  16. ^ a b Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A (Sep 2008). "PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex". Genes & Development 22 (18): 2496–506. doi:10.1101/gad.1676108. PMC 2546691. PMID 18794347. 
  17. ^ a b Higa L, Mihaylov I, Banks D, 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. 
  18. ^ a b Hu J, Xiong Y (Feb 2006). "An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage". The Journal of Biological Chemistry 281 (7): 3753–6. doi:10.1074/jbc.C500464200. PMID 16407242. 
  19. ^ a b c Lee J, Shieh J, Zhang J, Liu L, Zhang Y, Eom J et al. (May 2013). "Improved ex vivo expansion of adult hematopoietic stem cells by overcoming CUL4-mediated degradation of HOXB4". Blood 121 (20): 4082–9. doi:10.1182/blood-2012-09-455204. PMC 3656448. PMID 23520338. 
  20. ^ a b Zhang Y, Morrone G, Zhang J, Chen X, Lu X, Ma L et al. (Nov 2003). "CUL-4A stimulates ubiquitylation and degradation of the HOXA9 homeodomain protein". The EMBO Journal 22 (22): 6057–67. doi:10.1093/emboj/cdg577. PMC 275435. PMID 14609952. 
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  24. ^ "cBioPortal for Cancer Genomics". 
  25. ^ Li T, Hung M, Wang Y, Mao J, Tan J, Jahan K et al. (Mar 2011). "Transgenic mice for cre-inducible overexpression of the Cul4A gene". Genesis 49 (3): 134–41. doi:10.1002/dvg.20708. PMC 3285554. PMID 21381181. 
  26. ^ a b Ulane C, Kentsis A, Cruz C, Parisien J, Schneider K, Horvath C (Aug 2005). "Composition and assembly of STAT-targeting ubiquitin ligase complexes: paramyxovirus V protein carboxyl terminus is an oligomerization domain". Journal of Virology 79 (16): 10180–9. doi:10.1128/JVI.79.16.10180-10189.2005. PMC 1182666. PMID 16051811. 
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  38. ^ Min K, Hwang J, Lee J, Park Y, Tamura T, Yoon J (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. 
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Further reading[edit]

  • Osaka F, Kawasaki H, Aida N, Saeki M, Chiba T, Kawashima S et al. (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 L, Manjeshwar S, Lu Y, Moore D, Ljung B, Kuo W et al. (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 J, Schottelius A, 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 et al. (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 et al. (May 2001). "Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome". Science 292 (5520): 1382–5. doi:10.1126/science.1059780. PMID 11337588. 
  • 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 et al. (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 K, Hwang J, Lee J, Park Y, Tamura T, Yoon J (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 et al. (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 L, Mihaylov I, Banks D, 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 I, O'Rourke K, Zhang Z, Dornan D, Arnott D, Deshaies R et al. (Feb 2004). "Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase". 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 C, 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 et al. (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.