Denticleless protein homolog

Definition:

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. CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication. CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing. KMT5A degradation is also important for a proper regulation of mechanisms such as TGF-beta signaling, cell cycle progression, DNA repair and cell migration. 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. The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1.

References:

[1]. Stephane Angers, et al. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature. 2006 Oct 5;443(7111):590-3. [Content Brief]

[2]. Christopher L Sansam, et al. DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. Genes Dev. 2006 Nov 15;20(22):3117-29. [Content Brief]

[3]. Kenta Terai, et al. CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Mol Cell. 2010 Jan 15;37(1):143-9. [Content Brief]

[4]. Ukhyun Jo, et al. PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress. PLoS Genet. 2016 Dec 1;12(12):e1006465. [Content Brief]

[5]. Scott A Stuart, et al. Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells. J Biol Chem. 2009 May 29;284(22):15061-70. [Content Brief]

[6]. Youngjo Kim, et al. The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes Dev. 2008 Sep 15;22(18):2507-19. [Content Brief]

[7]. Mario Rossi, et al. 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. [Content Brief]

[8]. Agathe Bacquin, et al. 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. [Content Brief]

[9]. Tarek Abbas, et al. PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Genes Dev. 2008 Sep 15;22(18):2496-506. [Content Brief]

[10]. Tarek Abbas, et al. CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration. Mol Cell. 2013 Mar 28;49(6):1147-58. [Content Brief]

[11]. Leigh Ann Higa, et al. 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. [Content Brief]

[12]. Xin Tong, et al. 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. [Content Brief]

[13]. Jianping Jin, et al. 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. [Content Brief]

[14]. Hideo Nishitani, et al. 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. [Content Brief]

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