A Family of Diverse Cul4-Ddb1-Interacting Proteins Includes Cdt2, which Is Required for S Phase Destruction of the Replication Factor Cdt1

Jin, Jianping; Arias, Emily E.; Chen, Jing; Harper, J. Wade; Walter, Johannes C.

doi:10.1016/j.molcel.2006.08.010

Cited by 553 publications

(768 citation statements)

References 34 publications

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“…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 supporting

confidence: 85%

“…We favor the former model because there is strong evidence that the CUL4-DDB1 ligase plays multiple roles in the DNA damage response. We, and others, have shown that the DNA-damage-induced degradation of CDT1 or Spd1 is absolutely dependent on the human (CUL4-DDB1-DTL) or S. pombe (Pcu4-Ddb1-Cdt2) versions of the DTL-containing complex (Liu et al 2005;Higa et al 2006;Jin et al 2006). Additionally, CUL4-DDB1 ligases that include two other substrate recognition proteins, CSA or DDB2, are also modulated by DNA damage and play essential roles in the repair of ultraviolet (UV)-damaged DNA.…”

Section: Dtl Is Required For the Early G2/m Dna Damage Checkpointmentioning

confidence: 81%

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

Sansam¹,

Shepard²,

Lai³

et al. 2006

Genes Dev.

148

150

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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.

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

confidence: 85%

Section: Dtl Is Required For the Early G2/m Dna Damage Checkpointmentioning

confidence: 81%

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

Sansam¹,

Shepard²,

Lai³

et al. 2006

Genes Dev.

148

150

View full text Add to dashboard Cite

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“…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

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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.

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“…However, HBx does not cause Cdt1 to accumulate nor does it appear to trigger DNA re-replication as observed on DDB1 depletion. 28,29 Furthermore, genetic 9 and recent crystallographic studies (Ning Zheng, personal communication) revealed that HBx and the simian virus 5 V (SV5-V) protein, which is known to hijack DDB1 to target the STAT 1 factor of the interferon pathway for proteasomal degradation, 30 do interact with DDB1 in a strikingly similar manner. Thus, were HBx to act by blocking DDB1, one would expect SV5-V to do the same, yet SV5-V lacks any HBx activities.…”

mentioning

confidence: 99%

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

Lluesma¹,

Schaeffer²,

Robert³

et al. 2008

Hepatology

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Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), but its role in the transformation process remains unclear. HBV encodes a small protein, known as HBx, which is required for infection and has been implicated in hepatocarcinogenesis. Here we show that HBx induces lagging chromosomes during mitosis, which in turn leads to formation of aberrant mitotic spindles and multinucleated cells. These effects require the binding of HBx to UV-damaged DNA binding protein 1 (DDB1), a protein involved in DNA repair and cell cycle regulation, and are unexpectedly attributable to HBx interfering with S-phase progression and not directly with mitotic events. HBx also affects S-phase and induces lagging chromosomes when expressed from its natural viral context and, consequently, exhibits deleterious activities in dividing, but not quiescent, hepatoma cells. Conclusion: In addition to its reported role in promoting HBV replication, the binding of HBx to DDB1 may induce genetic instability in regenerating hepatocytes and thereby contribute to HCC development, thus making this HBV-host protein interaction an attractive target for new therapeutic intervention. (HEPATOLOGY 2008;48:1467-1476.)H epatocellular carcinoma (HCC) is the fifth most frequent cancer in humans, accounting for nearly 1 million deaths annually, and is mainly the consequence of chronic hepatitis B virus (HBV) infection. 1 HBV encodes a small regulatory protein, termed HBx, which is essential for virus replication in vivo and is expressed during chronic infection. 2 HBx has also been implicated in hepatocarcinogenesis. HBx is conserved among all mammalian hepatitis viruses that cause liver cancer in their hosts, whereas no counterpart exists in the non-oncogenic avian hepatitis viruses. Evidence derived from tumor sample analysis, cell culture, and transgenic animal studies collectively supports a role for HBx in HCC development. 3,4 However, the mechanism by which HBx may contribute to hepatocyte transformation remains obscure.In cell culture, HBx exhibits many activities, including an ability to stimulate HBV replication and to interfere with cell cycle progression, and it is believed to do so through interaction with cellular proteins. 2 Among these is UV-damaged DNA binding protein 1 (DDB1), a highly conserved 127-kDa protein that is also targeted by other viral regulatory proteins (see Discussion) and that functions as a subunit of an E3 ubiquitin ligase complex, in which it serves an adapter function to select specific targets for ubiquitin-dependent proteolysis. 5 Previous work demonstrated that HBx stimulates HBV genome replication by binding to DDB1 in the nuclear compartment of cells. 6 A nuclear interaction with DDB1 is also required for HBx to interfere with cell viability. 7 A similar DDB1-binding dependent cytotoxic activity has been re-

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A Family of Diverse Cul4-Ddb1-Interacting Proteins Includes Cdt2, which Is Required for S Phase Destruction of the Replication Factor Cdt1

Cited by 553 publications

References 34 publications

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

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

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

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

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