Molecular architecture and assembly of the DDB1–CUL4A ubiquitin ligase machinery

Angers, Stéphane; Li, Ti; Yi, Xianhua; MacCoss, Michael J.; Moon, Randall T.; Zheng, Ning

doi:10.1038/nature05175

Cited by 592 publications

(731 citation statements)

References 26 publications

Supporting

Mentioning

703

Contrasting

Order By: Relevance

“…CPSF-160 also bears weak sequence homology with the ubiquitin ligase DDB1, for which structural information has been obtained [97,98]. DDB1 contains three β-propellers (each with 7 repeats) and a C-terminal domain.…”

Section: Cpsf-160 (Cft1p/yhh1p)mentioning

confidence: 99%

Protein factors in pre-mRNA 3′-end processing

Mandel

Bai

Tong

2007

Cell. Mol. Life Sci.

364

482

View full text Add to dashboard Cite

Most eukaryotic mRNA precursors (pre-mRNAs) must undergo extensive processing, including cleavage and polyadenylation at the 3′-end. Processing at the 3′-end is controlled by sequence elements in the pre-mRNA (cis elements) as well as protein factors. Despite the seeming biochemical simplicity of the processing reactions, more than 14 proteins have been identified for the mammalian complex, and more than 20 proteins have been identified for the yeast complex. The 3′-end processing machinery also has important roles in transcription and splicing. The mammalian machinery contains several sub-complexes, including cleavage and polyadenylation specificity factor (CPSF), cleavage stimulation factor (CstF), cleavage factor I (CF I m ), and cleavage factor II (CF II m ). Additional protein factors include poly(A) polymerase (PAP), poly(A) binding protein (PABP), symplekin, and the C-terminal domain (CTD) of RNA polymerase II largest subunit. The yeast machinery includes cleavage factor IA (CF IA), cleavage factor IB (CF IB), and cleavage and polyadenylation factor (CPF).

show abstract

Section: Cpsf-160 (Cft1p/yhh1p)mentioning

confidence: 99%

Protein factors in pre-mRNA 3′-end processing

Mandel

Bai

Tong

2007

Cell. Mol. Life Sci.

364

482

View full text Add to dashboard Cite

show abstract

“…Mass spectrometry analysis revealed these proteins as DDB1 and VprBP, respectively (Figure 1a). VprBP and DDB1 have been shown to assemble with Cul4A and Roc1 to form an E3 ubiquitin ligase complex (Angers et al, 2006;He et al, 2006;Higa et al, 2006;Jin et al, 2006b). In addition, several peptides derived from DDA1, an additional component of the Cul4A ligase complex, were also identified from the purification (Table 1).…”

Section: Identification Of Vprbp and Ddb1 As Merlin-associated Proteinsmentioning

confidence: 99%

“…The Cullin E3 ligases have been shown to target a number of proteins for ubiquitination-dependent proteolysis via different adaptor proteins that afford specific substrate recognition (Higa and Zhang, 2007;Lee and Zhou, 2007). Recently, multiple WD40 domain-containing proteins were found to interact with DDB1 and serve as the substrate-recognition subunits of the CUL4-DDB1 ubiquitin ligase complex (Angers et al, 2006;He et al, 2006;Higa et al, 2006;Jin et al, 2006b). One of these WD40 domain-containing proteins, VprBP/ DCAF1, contains four WD40 domains and a LisH domain.…”

Section: Introductionmentioning

confidence: 99%

VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

Huang

Chen

2008

Oncogene

View full text Add to dashboard Cite

Inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene function has been observed not only in familial schwannomas and other central nervous system tumors, but also in malignant tumors unrelated to the NF2 syndrome, indicating a broader role of NF2 in human tumorigenesis. The NF2-encoded protein Merlin is closely related to the Ezrin-Radixin-Moesin family of membrane/ cytoskeleton linker proteins, and has been demonstrated to suppress tumor growth by inhibiting extracellular signal-regulated kinase (ERK) and Rac1 activation. Interestingly, serum deprivation has been shown to regulate Merlin at the protein level, however, exactly how such condition affects Merlin remains elusive. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasomemediated degradation. Consistently, VprBP depletion abolished the in vivo interaction of Merlin and Roc1-Cullin4A-DDB1, which resulted in Merlin stabilization and inhibited ERK and Rac activation. Together, our data revealed a novel regulatory mechanism for the tumor suppressor function of Merlin.

show abstract

“…Additionally, these data suggest that the cell cycle defects that we have observed in undamaged, DTL-depleted cells are entirely caused by the deregulation of CDT1. Contemporaneous with our study, others have shown that DTL/CDT2 is one of several DDB1-and CUL4-associated factors (DCAFs) and that DTL/CDT2 is required for CDT1 degradation (Angers et al 2006;Higa et al 2006;Jin et al 2006). …”

Section: A Critical Role For Dtl In Preventing Rereplication Through mentioning

confidence: 99%

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint

Sansam¹,

Shepard²,

Lai³

et al. 2006

Genes Dev.

151

150

View full text Add to dashboard Cite

Checkpoint genes maintain genomic stability by arresting cells after DNA damage. Many of these genes also control cell cycle events in unperturbed cells. By conducting a screen for checkpoint genes in zebrafish, we found that dtl/cdt2 is an essential component of the early, radiation-induced G2/M checkpoint. We subsequently found that dtl/cdt2 is required for normal cell cycle control, primarily to prevent rereplication. Both the checkpoint and replication roles are conserved in human DTL. Our data indicate that the rereplication reflects a requirement for DTL in regulating CDT1, a protein required for prereplication complex formation. CDT1 is degraded in S phase to prevent rereplication, and following DNA damage to prevent origin firing. We show that DTL associates with the CUL4-DDB1 E3 ubiquitin ligase and is required for CDT1 down-regulation in unperturbed cells and following DNA damage. The cell cycle defects of Dtl-deficient zebrafish are suppressed by reducing Cdt1 levels. In contrast, the early G2/M checkpoint defect appears to be Cdt1-independent. Thus, DTL promotes genomic stability through two distinct mechanisms. First, it is an essential component of the CUL4-DDB1 complex that controls CDT1 levels, thereby preventing rereplication. Second, it is required for the early G2/M checkpoint.

show abstract

Molecular architecture and assembly of the DDB1–CUL4A ubiquitin ligase machinery

Cited by 592 publications

References 26 publications

Protein factors in pre-mRNA 3′-end processing

Protein factors in pre-mRNA 3′-end processing

VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint

Contact Info

Product

Resources

About