Kaposi's Sarcoma-Associated Herpesvirus LANA-1 Interacts with the Short Variant of BRD4 and Releases Cells from a BRD4- and BRD2/RING3-Induced G
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            Cell CycleArrest

Ottinger, Matthias; Christalla, Thomas; Nathan, Kavita; Brinkmann, Melanie M.; Viejo‐Borbolla, Abel; Schulz, Thomas F.

doi:10.1128/jvi.00804-06

Cited by 135 publications

(171 citation statements)

References 55 publications

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“…The C-terminal region comprising the last 20 residues of LANA-1 (residues 1139-1162) is sufficient for interacting with the BRD4-ET domain (Ottinger et al 2006). Furthermore, the basic (pI ¼ 10.82) stretch of residues 1134-1143 (SSIVKFKKPL) was reported to be indispensable for the BRD4-ET interaction.…”

Section: Binding Analysismentioning

confidence: 99%

“…Recent studies showed that the ET domain of BRD4, and its homologs in BRD2 and BRD3, directly interact with Kaposi's sarcoma-associated herpesvirus-encoded latencyassociated nuclear antigen 1 (LANA-1) (Platt et al 1999;Viejo-Borbolla et al 2005;Ottinger et al 2006;You et al 2006). The C-terminal region comprising the last 20 residues of LANA-1 (residues 1139-1162) is sufficient for interacting with the BRD4-ET domain (Ottinger et al 2006).…”

Section: Binding Analysismentioning

confidence: 99%

“…For example, the C-terminal region of yeast Bdf1 containing an ET domain is responsible for the interaction with the Taf67 (TAF7) subunit of TFIID (Matangkasombut et al 2000). The C-terminal region of BRD4 containing the ET domain also interacts with Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen 1 (LANA-1) (Ottinger et al 2006;You et al 2006). However, the molecular mechanism for these interactions remained elusive because of the lack of structural information for the ET domain.…”

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confidence: 99%

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Solution structure of the extraterminal domain of the bromodomain‐containing protein BRD4

et al. 2008

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BRD4, which is a member of the BET (bromodomains and extraterminal) protein family, interacts preferentially with acetylated chromatin and possesses multiple cellular functions in meiosis, embryonic development, the cell cycle, and transcription. BRD4 and its family members contain two bromodomains known to bind acetylated lysine, and a conserved ET domain whose function is unclear. Here we show the solution structure of the ET domain of mouse BRD4, which provides the first threedimensional structure of an ET domain in the BET family. We determined the NMR structure of BRD4-ET with a root-mean-square deviation of 0.41 Å for the backbone atoms in the structured region of residues 608-676 on the basis of 1793 upper distance limits derived from NOE intensities measured in three-dimensional NOESY spectra. The structure of the BRD4-ET domain comprises three a-helices and a characteristic loop region of an irregular but well-defined structure. A DALI search revealed no close structural homologs in the current Protein Data Bank. The BRD4-ET structure has an acidic patch that forms a continuous ridge with a hydrophobic cleft, which may interact with other proteins and/or DNA. Abbreviations: BET, bromodomain and extraterminal; BRD4, bromodomain-containing protein 4; ET, extraterminal; HSQC, heteronuclear single quantum coherence; LANA-1, latency-associated nuclear antigen-1; NOE, nuclear Overhauser effect; NOESY, NOE spectroscopy; PCR, polymerase chain reaction; RMSD, root-mean-square deviation; TEV, tobacco etch virus.Article and publication are at

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Section: Binding Analysismentioning

confidence: 99%

Section: Binding Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Solution structure of the extraterminal domain of the bromodomain‐containing protein BRD4

et al. 2008

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“…The BRD4 BD and the flanking extra-terminal (ET) domain also participate in interactions with other proteins, including P-TEF-b Yang et al, 2005), through which BRD4 stimulates RNA-polymerase II transcriptional activity; and LANA-1 proteins (Ottinger et al, 2006), which may facilitate the attachment of human herpesvirus 8 to chromosomally associated BRD4 during mitotic segregation. The ET domain of BRD3, which is closely related to BRD4 in structure, also binds LANA-1 (Ottinger et al, 2006). Overexpression of BRD4 perturbs cell cycle progression, a phenotype that may be related to additional interactions with SPA-1, a Rap GTPase-activating protein (Farina et al, 2004), and replication factor C (Maruyama et al, 2002).…”

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confidence: 99%

BRD–NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells

et al. 2007

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An unusual group of carcinomas, here termed nuclear protein in testis (NUT) midline carcinomas (NMC), are characterized by translocations that involve NUT, a novel gene on chromosome 15. In about 2/3rds of cases, NUT is fused to BRD4 on chromosome 19. Using a candidate gene approach, we identified two NMCs harboring novel rearrangements that result in the fusion of NUT to BRD3 on chromosome 9. The BRD3-NUT fusion gene encodes a protein composed of two tandem chromatin-binding bromodomains, an extra-terminal domain, a bipartite nuclear localization sequence, and almost the entirety of NUT that is highly homologous to BRD4-NUT. The function of NUT is unknown, but here we show that NUT contains nuclear localization and export sequences that promote nuclearcytoplasmic shuttling via a leptomycin-sensitive pathway. In contrast, BRD3-NUT and BRD4-NUT are strictly nuclear, implying that the BRD moiety retains NUT in the nucleus via interactions with chromatin. Consistent with this idea, FRAP studies show that BRD4, BRD4-NUT and BRD3-NUT have significantly slower rates of lateral nuclear diffusion than that of NUT. To investigate the functional role of BRD-NUT fusion proteins in NMCs, we investigated the effects of siRNA-induced BRD3-NUT and BRD4-NUT withdrawal. Silencing of these proteins in NMC cell lines resulted in squamous differentiation and cell cycle arrest. Together, these data suggest that BRD-NUT fusion proteins contribute to carcinogenesis by associating with chromatin and interfering with epithelial differentiation.

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“…LANA is a multifunctional protein; it regulates a variety of cellular activities including gene transcription, DNA replication, and signaling pathways involved in cell proliferation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Kaposi Sarcoma (Ks)mentioning

confidence: 99%

The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence

Tan

Juillard

et al. 2015

Journal of Biological Chemistry

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Background: KSHV LANA binds virus DNA to mediate episome maintenance. Results: Mutating the novel LANA DNA binding domain (DBD) positive electrostatic patch engenders replication and episome persistence deficiencies. Conclusion: The LANA positive patch, possibly acting through a cell partner, is important for episome maintenance. Significance: Strategies that interfere with LANA positive patch function may allow future disruption of KSHV latency.

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Kaposi's Sarcoma-Associated Herpesvirus LANA-1 Interacts with the Short Variant of BRD4 and Releases Cells from a BRD4- and BRD2/RING3-Induced G ₁ Cell CycleArrest

Cited by 135 publications

References 55 publications

Solution structure of the extraterminal domain of the bromodomain‐containing protein BRD4

Solution structure of the extraterminal domain of the bromodomain‐containing protein BRD4

BRD–NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells

The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence

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Kaposi's Sarcoma-Associated Herpesvirus LANA-1 Interacts with the Short Variant of BRD4 and Releases Cells from a BRD4- and BRD2/RING3-Induced G 1 Cell CycleArrest

Cited by 135 publications

References 55 publications

Solution structure of the extraterminal domain of the bromodomain‐containing protein BRD4

Solution structure of the extraterminal domain of the bromodomain‐containing protein BRD4

BRD–NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells

The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence

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Resources

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Kaposi's Sarcoma-Associated Herpesvirus LANA-1 Interacts with the Short Variant of BRD4 and Releases Cells from a BRD4- and BRD2/RING3-Induced G ₁ Cell CycleArrest