| Structural highlights
Function
DDB1_HUMAN Required for DNA repair. Binds to DDB2 to form the UV-damaged DNA-binding protein complex (the UV-DDB complex). The UV-DDB complex may recognize UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches. Also appears to function as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1. DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair. DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR). May also play a role in ubiquitination of CDKN1B/p27kip when associated with CUL4 and SKP2.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]
Publication Abstract from PubMed
Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies. IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also known as CRL4CRBN) E3 ubiquitin ligase, and inhibit ubiquitination of endogenous CRL4CRBN substrates. Unexpectedly, IMiDs also repurpose the ligase to target new proteins for degradation. Lenalidomide induces degradation of the lymphoid transcription factors Ikaros and Aiolos (also known as IKZF1 and IKZF3), and casein kinase 1alpha (CK1alpha), which contributes to its clinical efficacy in the treatment of multiple myeloma and 5q-deletion associated myelodysplastic syndrome (del(5q) MDS), respectively. How lenalidomide alters the specificity of the ligase to degrade these proteins remains elusive. Here we present the 2.45 A crystal structure of DDB1-CRBN bound to lenalidomide and CK1alpha. CRBN and lenalidomide jointly provide the binding interface for a CK1alpha beta-hairpin-loop located in the kinase N-lobe. We show that CK1alpha binding to CRL4CRBN is strictly dependent on the presence of an IMiD. Binding of IKZF1 to CRBN similarly requires the compound and both, IKZF1 and CK1alpha, use a related binding mode. Our study provides a mechanistic explanation for the selective efficacy of lenalidomide in del(5q) MDS therapy. We anticipate that high-affinity protein-protein interactions induced by small molecules will provide opportunities for drug development, particularly for targeted protein degradation.
Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4 ubiquitin ligase.,Petzold G, Fischer ES, Thoma NH Nature. 2016 Feb 24. doi: 10.1038/nature16979. PMID:26909574[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Hu J, McCall CM, Ohta T, Xiong Y. Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol. 2004 Oct;6(10):1003-9. Epub 2004 Sep 26. PMID:15448697 doi:10.1038/ncb1172
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- ↑ Sugasawa K, Okuda Y, Saijo M, Nishi R, Matsuda N, Chu G, Mori T, Iwai S, Tanaka K, Tanaka K, Hanaoka F. UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex. Cell. 2005 May 6;121(3):387-400. PMID:15882621 doi:10.1016/j.cell.2005.02.035
- ↑ Kulaksiz G, Reardon JT, Sancar A. Xeroderma pigmentosum complementation group E protein (XPE/DDB2): purification of various complexes of XPE and analyses of their damaged DNA binding and putative DNA repair properties. Mol Cell Biol. 2005 Nov;25(22):9784-92. PMID:16260596 doi:10.1128/MCB.25.22.9784-9792.2005
- ↑ Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T. Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. EMBO J. 2006 Mar 8;25(5):1126-36. Epub 2006 Feb 16. PMID:16482215 doi:7601002
- ↑ He YJ, McCall CM, Hu J, Zeng Y, Xiong Y. DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases. Genes Dev. 2006 Nov 1;20(21):2949-54. PMID:17079684 doi:20/21/2949
- ↑ Hu J, Xiong Y. An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage. J Biol Chem. 2006 Feb 17;281(7):3753-6. Epub 2006 Jan 3. PMID:16407242 doi:10.1074/jbc.C500464200
- ↑ Senga T, Sivaprasad U, Zhu W, Park JH, Arias EE, Walter JC, Dutta A. PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination. J Biol Chem. 2006 Mar 10;281(10):6246-52. Epub 2006 Jan 9. PMID:16407252 doi:M512705200
- ↑ Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell. 2006 May 5;22(3):383-94. PMID:16678110 doi:S1097-2765(06)00230-9
- ↑ Lovejoy CA, Lock K, Yenamandra A, Cortez D. DDB1 maintains genome integrity through regulation of Cdt1. Mol Cell Biol. 2006 Nov;26(21):7977-90. Epub 2006 Aug 28. PMID:16940174 doi:MCB.00819-06
- ↑ Higa LA, Wu M, Ye T, Kobayashi R, Sun H, Zhang H. CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nat Cell Biol. 2006 Nov;8(11):1277-83. Epub 2006 Oct 15. PMID:17041588 doi:10.1038/ncb1490
- ↑ Kapetanaki MG, Guerrero-Santoro J, Bisi DC, Hsieh CL, Rapic-Otrin V, Levine AS. The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2588-93. Epub 2006 Feb 10. PMID:16473935 doi:10.1073/pnas.0511160103
- ↑ Guerrero-Santoro J, Kapetanaki MG, Hsieh CL, Gorbachinsky I, Levine AS, Rapic-Otrin V. The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A. Cancer Res. 2008 Jul 1;68(13):5014-22. PMID:18593899 doi:68/13/5014
- ↑ Hu J, Zacharek S, He YJ, Lee H, Shumway S, Duronio RJ, Xiong Y. WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase. Genes Dev. 2008 Apr 1;22(7):866-71. doi: 10.1101/gad.1624008. PMID:18381890 doi:10.1101/gad.1624008
- ↑ Huang J, Chen J. VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. Oncogene. 2008 Jul 3;27(29):4056-64. Epub 2008 Mar 10. PMID:18332868 doi:onc200844
- ↑ Petzold G, Fischer ES, Thoma NH. Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4 ubiquitin ligase. Nature. 2016 Feb 24. doi: 10.1038/nature16979. PMID:26909574 doi:https://dx.doi.org/10.1038/nature16979
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