DDB1- and CUL4-associated factor 15 (DCAF15) is a substrate recognition subunit that forms the CRL4 complex with CUL4A/B, RBX1, and DDB1 [1]. DCAF15 is a member of the WD40 domain-containing proteins, which serve as the substrate receptors in the CUL4-DDB1 E3 ligase [2]. Studies have shown that the sensitivity of hematopoietic cancer cell lines to certain compounds correlates with the level of DCAF15 expression, indicating its role in cancer cell response to treatment [3]. Unlike most other DCAFs, DCAF15 does not contain a canonical WD40 β-propeller fold and lacks homology to any other CRL substrate receptor [4]. DDB1 functions as a critical factor for CUL4-ROC ligases and acts as a linker to bridge a substrate receptor to CUL4, highlighting its role in assembling the CRL4 complexes [5][6].
Furthermore, DCAFs, including DCAF15, are essential for the versatile CUL4-DDB1 core ubiquitin ligase, and they serve as substrate recognition subunits, dictating the specificity of the ubiquitination process in different organisms [7][8]. Additionally, DDB1 and CUL4, along with their associated factors, have been implicated in various cellular functions, including ubiquitylation of histones, DNA repair, and regulation of protein ubiquitination and cellular processes [9][10][11].
References:
[1] S. Kim, S. Jo, J. Cho, M. Yu, H. Shin, J. Kimet al., "Aryl sulfonamides induce degradation of aryl hydrocarbon receptor nuclear translocator through crl4dcaf15 e3 ligase", Molecules and Cells, vol. 43, no. 11, p. 935-944, 2020. https://doi.org/10.14348/molcells.2020.0122
[2] Z. Sun, D. Zhou, J. Yang, & D. Zhang, "Doxorubicin promotes breast cancer cell migration and invasion via dcaf13", Febs Open Bio, vol. 12, no. 1, p. 221-230, 2021. https://doi.org/10.1002/2211-5463.13330
[3] R. Assi, H. Kantarjian, T. Kadia, N. Pemmaraju, E. Jabbour, N. Jainet al., "Final results of a phase 2, open‐label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome", Cancer, vol. 124, no. 13, p. 2758-2765, 2018. https://doi.org/10.1002/cncr.31398
[4] T. Faust, H. Yoon, R. Nowak, K. Donovan, Z. Li, Q. Caiet al., "Structural complementarity facilitates e7820-mediated degradation of rbm39 by dcaf15",, 2019. https://doi.org/10.1101/738534
[5] Y. He, C. McCall, J. Hu, Y. Zeng, & Y. Xiong, "Ddb1 functions as a linker to recruit receptor wd40 proteins to cul4–roc1 ubiquitin ligases", Genes & Development, vol. 20, no. 21, p. 2949-2954, 2006. https://doi.org/10.1101/gad.1483206
[6] T. Uehara, Y. Minoshima, K. Sagane, N. Sugi, K. Mitsuhashi, N. Yamamotoet al., "Selective degradation of splicing factor caperα by anticancer sulfonamides", Nature Chemical Biology, vol. 13, no. 6, p. 675-680, 2017. https://doi.org/10.1038/nchembio.2363
[7] J. Lee and P. Zhou, "Dcafs, the missing link of the cul4-ddb1 ubiquitin ligase", Molecular Cell, vol. 26, no. 6, p. 775-780, 2007. https://doi.org/10.1016/j.molcel.2007.06.001
[8] H. Chen, X. Huang, G. Gusmaroli, W. Terzaghi, O. Lau, Y. Yanagawaet al., "arabidopsis cullin4-damaged dna binding protein 1 interacts with constitutively photomorphogenic1-suppressor of phya complexes to regulate photomorphogenesis and flowering time", The Plant Cell, vol. 22, no. 1, p. 108-123, 2010. https://doi.org/10.1105/tpc.109.065490
[9] J. Jin, E. Arias, J. Chen, J. Harper, & J. Walter, "A family of diverse cul4-ddb1-interacting proteins includes cdt2, which is required for s phase destruction of the replication factor cdt1", Molecular Cell, vol. 23, no. 5, p. 709-721, 2006. https://doi.org/10.1016/j.molcel.2006.08.010
[10] Y. Zhang, S. Feng, F. Chen, H. Chen, J. Wang, C. McCallet al., "arabidopsisddb1-cul4 associated factor1 forms a nuclear e3 ubiquitin ligase with ddb1 and cul4 that is involved in multiple plant developmental processes", The Plant Cell, vol. 20, no. 6, p. 1437-1455, 2008. https://doi.org/10.1105/tpc.108.058891
[11] C. McCall, P. Marval, P. Chastain, S. Jackson, Y. He, Y. Kotakeet al., "Human immunodeficiency virus type 1 vpr-binding protein vprbp, a wd40 protein associated with the ddb1-cul4 e3 ubiquitin ligase, is essential for dna replication and embryonic development", Molecular and Cellular Biology, vol. 28, no. 18, p. 5621-5633, 2008. https://doi.org/10.1128/mcb.00232-08
