CUL4B

CUL4B
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2DO7, 4A0C, 4A0L, 4A64
Identifiers
Aliases	CUL4B , CUL-4B, MRXHF2, MRXS15, MRXSC, SFM2, cullin 4B
External IDs	OMIM: 300304 MGI: 1919834 HomoloGene: 2660 GeneCards: CUL4B
Gene location (Human) Chr. X chromosome (human) [1] Band Xq24 Start 120,505,920 bp [1] End 120,604,074 bp [1]
Gene location (Mouse) Chr. X chromosome (mouse) [2] Band X|X A3.3 Start 37,622,151 bp [2] End 37,665,073 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sperm corpus epididymis caput epididymis Achilles tendon ganglionic eminence stromal cell of endometrium superficial temporal artery anterior pituitary seminal vesicula tibia Top expressed in secondary oocyte seminiferous tubule medullary collecting duct spermatid maxillary prominence abdominal wall aortic valve supraoptic nucleus yolk sac somite More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ubiquitin protein ligase activity damaged DNA binding protein binding ubiquitin protein ligase binding Cellular component cullin-RING ubiquitin ligase complex nucleoplasm extracellular exosome nucleus cytosol Cul4B-RING E3 ubiquitin ligase complex Cul4-RING E3 ubiquitin ligase complex SCF ubiquitin ligase complex Biological process positive regulation of protein catabolic process nucleotide-excision repair, DNA damage recognition ubiquitin-dependent protein catabolic process histone H2A monoubiquitination cellular response to DNA damage stimulus positive regulation of G1/S transition of mitotic cell cycle global genome nucleotide-excision repair cell cycle transcription-coupled nucleotide-excision repair nucleotide-excision repair, DNA incision neuron projection development UV-damage excision repair nucleotide-excision repair, preincision complex assembly nucleotide-excision repair, DNA incision, 3'-to lesion nucleotide-excision repair, DNA incision, 5'-to lesion nucleotide-excision repair, DNA duplex unwinding DNA repair nucleotide-excision repair, preincision complex stabilization post-translational protein modification proteasomal protein catabolic process protein ubiquitination G1/S transition of mitotic cell cycle SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proteasome-mediated ubiquitin-dependent protein catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8450 72584 Ensembl ENSG00000158290 ENSMUSG00000031095 UniProt Q13620 A2A432 RefSeq (mRNA) NM_001079872 NM_003588 NM_001330624 NM_001369145 NM_001110142 NM_028288 RefSeq (protein) NP_001073341 NP_001317553 NP_003579 NP_001356074 NP_001103612 NP_082564 Location (UCSC) Chr X: 120.51 – 120.6 Mb Chr X: 37.62 – 37.67 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome. ^{[5] [6]} CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.

Structure

Human CUL4B is 913 amino acids long and shares a high degree of sequence identity (84%) with CUL4A with the exception of its unique N-terminal region. ^[7] The extreme N-terminus of CUL4B is disordered and, currently, it is unclear what structural and functional qualities it possesses. CUL4B binds to the beta-propeller of the DDB1 adaptor protein which interacts with numerous DDB1-CUL4-Associated Factors (DCAFs). This interaction is crucial for the recruitment of substrates to the ubiquitin ligase complex. At the C-terminal end, CUL4B 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 CUL4B - along with RBX1 and activated E2 enzymes - compose the catalytic core of CRL4B complexes. CUL4B 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. ^[8]

Functions

Cell cycle regulation and chromatin remodeling

CUL4B-based E3 ubiquitin ligase complexes often demonstrate overlapping activity with CUL4A-based complexes. Both CRL4 complexes utilize Cdt2 and the DNA processivity factor PCNA to induce the ubiquitination and degradation of replication licensing factor Cdt1 and cyclin-dependent kinase inhibitor p21 in a proteasome-dependent manner. ^{[9] [10]} CRL4^Cdt2 also degrades PCNA-bound PR-Set7/SET8, which is a histone 4 methyltransferase, and the p12 subunit of DNA polymerase δ, which is crucial for DNA replication. ^{[11] [12]} As a result, CRL4 complexes are able to control the onset of DNA replication, chromatin remodeling and progression through the cell cycle.

Mammalian embryonic development

Loss of Cul4b in mice causes embryonic lethality and defects in placental development. The extra-embryonic tissue of these developing mice also showed increased rates of apoptosis and a decrease in cell proliferation. When Cul4b deletion was limited to the epiblast (only in Sox2-expressing tissue), it was possible to generate living mice. ^[13]

Neurological development

Mice that do not express CUL4B in epiblast tissue demonstrate normal brain morphology but decrease number of parvalbumin (PV)-positive GABAergic interneurons - particularly in the dentate gyrus. ^[14] In these mice, certain dendritic features of hippocampal neurons were also affected by Cul4b loss, which may explain the observed increases in epileptic susceptibility and spatial learning defects. These phenotypes resembled features seen in patients with X-linked intellectual disability (see below).

Clinical significance

X-linked intellectual disability

Loss-of-function CUL4B mutation events have been discovered in numerous patients with X-linked intellectual disability, which is characterized by aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus and tremor. ^{[15] [16] [17]} CUL4B mutations have also been associated with malformations of cortical development. ^[18]

Viral pathogenesis

After HIV infects a cell, the virus "hijacks" either the CUL4B-DDB1 complex or the CUL4A-DDB1 complex via the same mechanism. Essentially, HIV proteins such as Vpr and Vpx bind to VPRBP (a DDB1-binding substrate receptor protein) and induce the ubiquitination and degradation of SAMHD1 and UNG2 to promote viral replication. ^[19] These proteins are not degraded by CRL4 complexes in the absence of virus.

Cancer

According to data from The Cancer Genome Atlas, CUL4B is mutated in 21% of pancreatic carcinomas with a recurring truncating mutation at amino acid 143. CUL4B is also mutated or amplified in 3-5% of lung cancers. The significance of these observed mutations has not been determined.

Thalidomide treatment

In 2010, Ito et al. reported that Cereblon, a DCAF protein, was a major target of the teratogenic compound thalidomide. ^[20] 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. ^{[21] [22]}

Interactions and substrates

Human CUL4B forms direct interactions with:

• RBX1 ^[23]
• CAND1 ^[24]
• DDB1 ^[25] and
• the COP9 signalosome ^[26]

Human CUL4B-DDB1-RBX1 complexes promote the ubiquitination of:

• Cdt1 ^{[9] [27]}
• p21 ^{[10] [28]}
• PR-Set7/SET8 ^[11]
• p12 subunit of DNA polymerase δ ^[12]
• SAMHD1† ^[19]
• UNG2† ^[19]
• IKZF1 ^{§ [21] [22]}
• IKZF3 ^{§ [21] [22]}

^†protein is a CRL4 substrate only when directed by viral proteins
^§protein is a CRL4 substrate only when directed by IMiDs

References

1. GRCh38: Ensembl release 89: ENSG00000158290 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031095 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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6. "Entrez Gene: CUL4B cullin 4B".
7. Fischer ES, Scrima A, Böhm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thomä NH (Nov 2011). "The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation". Cell. 147 (5): 1024–39. doi: 10.1016/j.cell.2011.10.035 . PMID   22118460. S2CID   17915668.
8. Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA (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.
9. 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.
10. Nishitani H, Shiomi Y, Iida H, Michishita M, Takami T, Tsurimoto T (Oct 2008). "CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation". The Journal of Biological Chemistry. 283 (43): 29045–52. doi: 10.1074/jbc.M806045200 . PMC   2662008 . PMID   18703516.
11. Jørgensen S, Eskildsen M, Fugger K, Hansen L, Larsen MS, Kousholt AN, Syljuåsen RG, Trelle MB, Jensen ON, Helin K, Sørensen CS (Jan 2011). "SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation". The Journal of Cell Biology. 192 (1): 43–54. doi:10.1083/jcb.201009076. PMC   3019552 . PMID   21220508.
12. Zhang S, Zhao H, Darzynkiewicz Z, Zhou P, Zhang Z, Lee EY, Lee MY (Oct 2013). "A novel function of CRL4(Cdt2): regulation of the subunit structure of DNA polymerase δ in response to DNA damage and during the S phase". The Journal of Biological Chemistry. 288 (41): 29550–61. doi: 10.1074/jbc.M113.490466 . PMC   3795253 . PMID   23913683.
13. Liu L, Yin Y, Li Y, Prevedel L, Lacy EH, Ma L, Zhou P (Aug 2012). "Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis". Cell Research. 22 (8): 1258–69. doi:10.1038/cr.2012.48. PMC   3411166 . PMID   22453236.
14. Chen CY, Tsai MS, Lin CY, Yu IS, Chen YT, Lin SR, Juan LW, Chen YT, Hsu HM, Lee LJ, Lin SW (Oct 2012). "Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation". Human Molecular Genetics. 21 (19): 4270–85. doi: 10.1093/hmg/dds261 . PMID   22763239.
15. Londin ER, Adijanto J, Philp N, Novelli A, Vitale E, Perria C, Serra G, Alesi V, Surrey S, Fortina P (2014). "Donor splice-site mutation in CUL4B is likely cause of X-linked intellectual disability". Am. J. Med. Genet. A. 164A (9): 2294–9. doi:10.1002/ajmg.a.36629. PMC   4404493 . PMID   24898194.
16. Zou Y, Liu Q, Chen B, Zhang X, Guo C, Zhou H, Li J, Gao G, Guo Y, Yan C, Wei J, Shao C, Gong Y (Mar 2007). "Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation". American Journal of Human Genetics. 80 (3): 561–6. doi:10.1086/512489. PMC   1821105 . PMID   17273978.
17. Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M (Feb 2007). "Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor". American Journal of Human Genetics. 80 (2): 345–52. doi:10.1086/511134. PMC   1785336 . PMID   17236139.
18. Vulto-van Silfhout AT, Nakagawa T, Bahi-Buisson N, Haas SA, Hu H, Bienek M, Vissers LE, Gilissen C, Tzschach A, Busche A, Müsebeck J, Rump P, Mathijssen IB, Avela K, Somer M, Doagu F, Philips AK, Rauch A, Baumer A, Voesenek K, Poirier K, Vigneron J, Amram D, Odent S, Nawara M, Obersztyn E, Lenart J, Charzewska A, Lebrun N, Fischer U, Nillesen WM, Yntema HG, Järvelä I, Ropers HH, de Vries BB, Brunner HG, van Bokhoven H, Raymond FL, Willemsen MA, Chelly J, Xiong Y, Barkovich AJ, Kalscheuer VM, Kleefstra T, de Brouwer AP (Jan 2015). "Variants in CUL4B are associated with cerebral malformations". Human Mutation. 36 (1): 106–17. doi:10.1002/humu.22718. PMC   4608231 . PMID   25385192.
19. Sharifi HJ, Furuya AK, Jellinger RM, Nekorchuk MD, de Noronha CM (Jun 2014). "Cullin4A and cullin4B are interchangeable for HIV Vpr and Vpx action through the CRL4 ubiquitin ligase complex". Journal of Virology. 88 (12): 6944–58. doi:10.1128/JVI.00241-14. PMC   4054339 . PMID   24719410.
20. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (Mar 2010). "Identification of a primary target of thalidomide teratogenicity". Science. 327 (5971): 1345––50. Bibcode:2010Sci...327.1345I. doi:10.1126/science.1177319. PMID   20223979. S2CID   17575104.
21. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG (Jan 2014). "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins". Science. 343 (6168): 305–9. Bibcode:2014Sci...343..305L. doi:10.1126/science.1244917. PMC   4070318 . PMID   24292623.
22. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL (Jan 2014). "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells". Science. 343 (6168): 301–5. Bibcode:2014Sci...343..301K. doi:10.1126/science.1244851. PMC   4077049 . PMID   24292625.
23. 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. S2CID   19371828.
24. Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (May 2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". J. Biol. Chem. 278 (18): 15905–10. doi: 10.1074/jbc.M213070200 . PMID   12609982.
25. Guerrero-Santoro J, Kapetanaki MG, Hsieh CL, Gorbachinsky I, Levine AS, Rapić-Otrin V (Jul 2008). "The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A". Cancer Research. 68 (13): 5014–22. doi: 10.1158/0008-5472.CAN-07-6162 . PMID   18593899.
26. Chew EH, Hagen T (Jun 2007). "Substrate-mediated regulation of cullin neddylation". The Journal of Biological Chemistry. 282 (23): 17032–40. doi: 10.1074/jbc.M701153200 . PMID   17439941.
27. Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T (Mar 2006). "Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis". The EMBO Journal. 25 (5): 1126–36. doi:10.1038/sj.emboj.7601002. PMC   1409712 . PMID   16482215.
28. 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.

External links

• Human CUL4B genome location and CUL4B gene details page in the UCSC Genome Browser .
• Overview of all the structural information available in the PDB for UniProt : Q13620 (Human Cullin-4B) at the PDBe-KB .

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (2003). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Res. 9 (3): 99–106. doi: 10.1093/dnares/9.3.99 . PMID   12168954.
• Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1998). "Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Res. 5 (3): 169–76. doi: 10.1093/dnares/5.3.169 . PMID   9734811.
• Wada H, Yeh ET, Kamitani T (1999). "Identification of NEDD8-conjugation site in human cullin-2". Biochem. Biophys. Res. Commun. 257 (1): 100–5. doi:10.1006/bbrc.1999.0339. PMID   10092517.
• Ohta T, Michel JJ, Schottelius AJ, Xiong Y (1999). "ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity". Mol. Cell. 3 (4): 535–41. doi: 10.1016/S1097-2765(00)80482-7 . PMID   10230407. S2CID   19371828.
• Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S, Tanaka K (2000). "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.
• Jones EA, Clement-Jones M, Wilson DI (2000). "JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype". J. Med. Genet. 37 (9): 658–62. doi:10.1136/jmg.37.9.658. PMC   1734694 . PMID   10978356.
• Zheng J, Yang X, Harrell JM, Ryzhikov S, Shim EH, Lykke-Andersen K, Wei N, Sun H, Kobayashi R, Zhang H (2003). "CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex". Mol. Cell. 10 (6): 1519–26. doi: 10.1016/S1097-2765(02)00784-0 . PMID   12504026.
• Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". J. Biol. Chem. 278 (18): 15905–10. doi: 10.1074/jbc.M213070200 . PMID   12609982.
• Higa LA, Mihaylov IS, Banks DP, Zheng J, Zhang H (2004). "Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint". Nat. Cell Biol. 5 (11): 1008–15. doi:10.1038/ncb1061. PMID   14578910. S2CID   26070877.
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–5. Bibcode:2004PNAS..10112130B. doi: 10.1073/pnas.0404720101 . PMC   514446 . PMID   15302935.
• Higa LA, Yang X, Zheng J, Banks D, Wu M, Ghosh P, Sun H, Zhang H (2006). "Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation". Cell Cycle. 5 (1): 71–7. doi: 10.4161/cc.5.1.2266 . PMID   16322693.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (2006). "Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC   1356129 . PMID   16344560.
• Senga T, Sivaprasad U, Zhu W, Park JH, Arias EE, Walter JC, Dutta A (2006). "PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination". J. Biol. Chem. 281 (10): 6246–52. doi: 10.1074/jbc.M512705200 . PMID   16407252.
• Li T, Santockyte R, Shen RF, Tekle E, Wang G, Yang DC, Chock PB (2006). "A general approach for investigating enzymatic pathways and substrates for ubiquitin-like modifiers". Arch. Biochem. Biophys. 453 (1): 70–4. doi:10.1016/j.abb.2006.03.002. PMID   16620772.
• Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y (2006). "Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage". Mol. Cell. 22 (3): 383–94. doi: 10.1016/j.molcel.2006.03.035 . PMID   16678110. S2CID   25677159.