Lentiviral Vpr usurps Cul4–DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle

Hrecka, Kasia; Gierszewska, Małgorzata; Srivastava, Smita; Kozaczkiewicz, Lukasz; Swanson, Selene K.; Florens, Laurence; Washburn, Michael P.; Skowroński, Jacek

doi:10.1073/pnas.0702102104

Cited by 209 publications

(253 citation statements)

References 52 publications

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“…4A). Interestingly, in contrast with a recent report showing that the expression level of p53 is relatively high in VprBP-depleted cells (11), our data demonstrated no detectable alteration in the p53 protein level after VprBP knockdown. In checking the transcription of p53-responsive genes, such as p21, Gadd45, Bax, Casp8, and Noxa, by qRT-PCR, we found that RNAi depletion of p53 led to a severe reduction in transcription after DNA damage, indicating that p53 is the major regulator of these genes (Fig.…”

Section: Vprbpcontrasting

confidence: 55%

“…Given this reversible nature of histone acetylation, cells need to employ additional factors that can recognize and lock in a distinct (de)acetylation status of promoter nucleosomes. In relation to the present study, the cellular depletion of VprBP leads to the increased expression of the p53 target gene p21 (11). These results raise questions about whether VprBP is able to downregulate p53-mediated transcription and, if so, how this would affect cellular responses to DNA damage.…”

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confidence: 57%

“…The direct interaction of tumor suppressor Merlin with VprBP is shown to be an integral part of the mechanism by which Merlin inhibits CUL4-DDB1 ubiquitin E3 ligase to suppress tumorigenesis (22). Furthermore, the observation that VprBP-depleted cells activate DNA damage checkpoints and increase the cellular level of CDK inhibitor p21 suggests that VprBP is involved in the control of cell cycle arrest and apoptosis (11).…”

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confidence: 99%

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Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

Kim

Heo

Choi

et al. 2012

Molecular and Cellular Biology

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HIV-1 Vpr-binding protein (VprBP) has been implicated in the regulation of both DNA replication and cell cycle progression, but its precise role remains unclear. Here we report that VprBP regulates the p53-induced transcription and apoptotic pathway. VprBP is recruited to p53-responsive promoters and suppresses p53 transactivation in the absence of stress stimuli. To maintain target promoters in an inactive state, VprBP stably binds to nucleosomes by recognizing unacetylated H3 tails. Promoterlocalized deacetylation of H3 tails is a prerequisite for VprBP to tether and act as a bona fide inhibitor at p53 target genes. VprBP knockdown leads to activation of p53 target genes and causes an increase in DNA damage-induced apoptosis. Moreover, phosphorylation of VprBP at serine 895 impairs the ability of VprBP to bind H3 tails and to repress p53 transactivation. Our results thus reveal a new role for VprBP in regulation of the p53 signaling pathway, as well as molecular mechanisms of cancer development related to VprBP misregulation. VprBP was first identified as a protein that can interact with HIV-1 viral protein R by coimmunoprecipitation assays (37). VprBP is a 1,507-amino-acid protein that contains conserved domains, including YXXY repeats, the Lis homology motif, and WD40 repeats. Despite the lack of molecular characterization of VprBP, recent studies suggest that VprBP can specifically associate with DDB1 to act as a substrate recognition subunit of the CUL4-DDB1 ubiquitin E3 ligase complex (12,20,26,33,36,38). Through binding to Vpr, VprBP allows Vpr to modulate the intrinsic catalytic activity of the CUL4-DDB1 complex, which in turn leads to the induction of G 2 phase cell cycle arrest in the virus-infected cells. The direct interaction of tumor suppressor Merlin with VprBP is shown to be an integral part of the mechanism by which Merlin inhibits CUL4-DDB1 ubiquitin E3 ligase to suppress tumorigenesis (22). Furthermore, the observation that VprBP-depleted cells activate DNA damage checkpoints and increase the cellular level of CDK inhibitor p21 suggests that VprBP is involved in the control of cell cycle arrest and apoptosis (11).p53 is an important tumor suppressor which induces either cell cycle arrest or apoptosis in response to DNA damage (27,30,34). p53 regulates these processes mainly by acting as a sequencespecific DNA binding factor that regulates transcription of a number of target genes. p53 regulates the transcription reaction, to a large extent, at the level of chromatin, which establishes a physical barrier for the binding of transcription factors to the promoter region of a target gene. The most dynamic parts of chromatin are amino-terminal domains (called histone "tails") of core histones, which protrude from the DNA. The major contributions of individual histone tails in gene transcription are made through their posttranslational modifications (3,18,21,29,35). Among various modifications, histone acetylation has been implicated as a critical mark for activation of p53 target genes (1,5,7,10,13...

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Section: Vprbpcontrasting

confidence: 55%

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confidence: 57%

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confidence: 99%

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Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

Kim

Heo

Choi

et al. 2012

Molecular and Cellular Biology

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“…One of these WD40 domain-containing proteins, VprBP/ DCAF1, contains four WD40 domains and a LisH domain. VprBP was originally identified due to its interaction with the Vpr protein from the human immunodeficiency virus, however, the physiological function and substrates of VprBP/DCAF1 are still unknown (Zhang et al, 2001;Belzile et al, 2007;Hrecka et al, 2007;Le Rouzic et al, 2007;Tan et al, 2007;Wen et al, 2007).…”

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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“…First, the best renowned activity of Vpr, its ability to mediate a G2 arrest of the cell cycle, depends on the activation of the ATR-mediated (ATR: ataxia telangiectasia mutated and Rad3 related) DNA damage response (22). G2 arrest requires Vpr binding to DCAF1, an adaptor of the Cul4A-DDB1 ubiquitin ligase, which is involved in DNA repair in noninfected cells (23)(24)(25)(26)(27)(28)(29). More recently, Vpr has been shown to activate the SLX4 complex (SLX4com) with the help of DCAF1 (21,30).…”

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confidence: 99%

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks. Vpr subverts the DDB1-cullin4-associatedfactor 1 (DCAF1) adaptor of the Cul4A ubiquitin ligase to trigger proteasomal degradation of HLTF. This event takes place rapidly after Vpr delivery to cells, before and independently of Vpr-mediated G2 arrest. HLTF is degraded in lymphocytic cells and macrophages infected with Vpr-expressing HIV-1. Our results reveal a previously unidentified strategy for HIV-1 to antagonize DNA repair in host cells.HIV | restriction factor | DNA repair | Vpr target | SILAC

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Lentiviral Vpr usurps Cul4–DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle

Cited by 209 publications

References 52 publications

Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

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

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

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