9c5u

Structural highlights

Function

DTL_HUMAN Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis. The DCX(DTL) complex, also named CRL4(CDT2) complex, mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2 (PubMed:16861906, PubMed:16949367, PubMed:16964240, PubMed:17085480, PubMed:18703516, PubMed:18794347, PubMed:18794348, PubMed:19332548, PubMed:20129063, PubMed:23478441, PubMed:23478445, PubMed:23677613, PubMed:27906959). CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication (PubMed:16861906, PubMed:16949367, PubMed:17085480). CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing (PubMed:18794348, PubMed:19332548). KMT5A degradation is also important for a proper regulation of mechanisms such as TGF-beta signaling, cell cycle progression, DNA repair and cell migration (PubMed:23478445). Most substrates require their interaction with PCNA for their polyubiquitination: substrates interact with PCNA via their PIP-box, and those containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to their degradation. In undamaged proliferating cells, the DCX(DTL) complex also promotes the 'Lys-164' monoubiquitination of PCNA, thereby being involved in PCNA-dependent translesion DNA synthesis (PubMed:20129063, PubMed:23478441, PubMed:23478445, PubMed:23677613). The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1 (PubMed:26431207).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]}

References

1. ↑ Higa LA, Banks D, Wu M, Kobayashi R, Sun H, Zhang H. L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage. Cell Cycle. 2006 Aug;5(15):1675-80. PMID:16861906 doi:10.4161/cc.5.15.3149
2. ↑ Jin J, Arias EE, Chen J, Harper JW, Walter JC. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell. 2006 Sep 1;23(5):709-21. PMID:16949367 doi:http://dx.doi.org/S1097-2765(06)00570-3
3. ↑ Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature. 2006 Oct 5;443(7111):590-3. PMID:16964240 doi:10.1038/nature05175
4. ↑ Sansam CL, Shepard JL, Lai K, Ianari A, Danielian PS, Amsterdam A, Hopkins N, Lees JA. DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. Genes Dev. 2006 Nov 15;20(22):3117-29. PMID:17085480 doi:10.1101/gad.1482106
5. ↑ Nishitani H, Shiomi Y, Iida H, Michishita M, Takami T, Tsurimoto T. CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation. J Biol Chem. 2008 Oct 24;283(43):29045-52. PMID:18703516 doi:10.1074/jbc.M806045200
6. ↑ Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A. PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Genes Dev. 2008 Sep 15;22(18):2496-506. PMID:18794347 doi:10.1101/gad.1676108
7. ↑ Kim Y, Starostina NG, Kipreos ET. The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes Dev. 2008 Sep 15;22(18):2507-19. PMID:18794348 doi:10.1101/gad.1703708
8. ↑ Stuart SA, Wang JY. Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells. J Biol Chem. 2009 May 29;284(22):15061-70. PMID:19332548 doi:10.1074/jbc.M808810200
9. ↑ Terai K, Abbas T, Jazaeri AA, Dutta A. CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Mol Cell. 2010 Jan 15;37(1):143-9. PMID:20129063 doi:10.1016/j.molcel.2009.12.018
10. ↑ Rossi M, Duan S, Jeong YT, Horn M, Saraf A, Florens L, Washburn MP, Antebi A, Pagano M. Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase. Mol Cell. 2013 Mar 28;49(6):1159-66. doi: 10.1016/j.molcel.2013.02.004. Epub 2013, Mar 7. PMID:23478441 doi:http://dx.doi.org/10.1016/j.molcel.2013.02.004
11. ↑ Abbas T, Mueller AC, Shibata E, Keaton M, Rossi M, Dutta A. CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration. Mol Cell. 2013 Mar 28;49(6):1147-58. doi: 10.1016/j.molcel.2013.02.003. Epub 2013, Mar 7. PMID:23478445 doi:http://dx.doi.org/10.1016/j.molcel.2013.02.003
12. ↑ Bacquin A, Pouvelle C, Siaud N, Perderiset M, Salomé-Desnoulez S, Tellier-Lebegue C, Lopez B, Charbonnier JB, Kannouche PL. The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells. Nucleic Acids Res. 2013 Jul;41(13):6501-13. PMID:23677613 doi:10.1093/nar/gkt397
13. ↑ Tong X, Zhang D, Guha A, Arthurs B, Cazares V, Gupta N, Yin L. CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1. PLoS One. 2015 Oct 2;10(10):e0139725. PMID:26431207 doi:10.1371/journal.pone.0139725
14. ↑ Jo U, Cai W, Wang J, Kwon Y, D'Andrea AD, Kim H. PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress. PLoS Genet. 2016 Dec 1;12(12):e1006465. doi: 10.1371/journal.pgen.1006465., eCollection 2016 Dec. PMID:27906959 doi:http://dx.doi.org/10.1371/journal.pgen.1006465