Interaction of Bovine Papillomavirus E2 Protein with Brd4 Stabilizes Its Association with Chromatin

McPhillips, Maria G.; Ozato, Keiko; McBride, Alison A.

doi:10.1128/jvi.79.14.8920-8932.2005

Cited by 99 publications

(130 citation statements)

References 60 publications

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“…This genometethering function of BPV-1 E2 (Lehman and Botchan 1998;Skiadopoulos and McBride 1998;Ilves et al 1999) can be adapted for plasmid maintenance in Saccharomy-ces cerevisiae, provided that E2-binding sites are created in the plasmid and mammalian Brd4 is additionally introduced into yeast (Brannon et al 2005). The association between Brd4 and BPV-1 E2 with chromatin appears to be stable and persists through both mitosis and interphase (McPhillips et al 2005). Since HPV E2 does not stably associate with mitotic chromosomes and seems to anchor on mitotic spindles during mitosis (Van Tine et al 2004), it remains to be investigated whether the genomic-tethering function of BPV-1 E2 can be applied to HPV E2 with respect to their functional interactions with Brd4.…”

Section: Discussionmentioning

confidence: 99%

Brd4 links chromatin targeting to HPV transcriptional silencing

et al. 2006

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The E2 protein encoded by human papillomaviruses (HPVs) inhibits expression of the viral E6 oncoprotein, which, in turn, regulates p53 target gene transcription. To identify cellular proteins involved in E2-mediated transcriptional repression, we isolated an E2 complex from human cells conditionally expressing HPV-11 E2. Surprisingly, the double bromodomain-containing protein Brd4, which is implicated in cell cycle control and viral genome segregation, was found associated with E2 and conferred on E2 the ability to inhibit AP-1-dependent HPV chromatin transcription in an E2-binding site- [Keywords: HPV; E2; AP-1; Brd4; chromatin transcription; gene silencing] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionmentioning

confidence: 99%

Brd4 links chromatin targeting to HPV transcriptional silencing

et al. 2006

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“…Most relevant to this study, Brd4 acts as an attachment site for the tethering of papilloma viral genomes to the mitotic chromosomes. The E2 protein of bovine papilloma virus (BPV) tethers the viral genome to mitotic chromosomes via bimodal interaction of its C-terminal DNA-binding domain with viral DNA and the N-terminal transactivation domain with the C-terminal region of Brd4 (40,41). This E2-Brd4 interaction plays a critical role for BPV genome segregation by ensuring that the BPV episomal DNA is retained in the nucleus after cell division.…”

Section: Discussionmentioning

confidence: 99%

BET proteins promote efficient murine leukemia virus integration at transcription start sites

Sharma¹,

Larue²,

Plumb³

et al. 2013

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

185

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The selection of chromosomal targets for retroviral integration varies markedly, tracking with the genus of the retrovirus, suggestive of targeting by binding to cellular factors. γ-Retroviral murine leukemia virus (MLV) DNA integration into the host genome is favored at transcription start sites, but the underlying mechanism for this preference is unknown. Here, we have identified bromodomain and extraterminal domain (BET) proteins (Brd2, -3, -4) as cellular-binding partners of MLV integrase. We show that purified recombinant Brd4(1-720) binds with high affinity to MLV integrase and stimulates correct concerted integration in vitro. JQ-1, a small molecule that selectively inhibits interactions of BET proteins with modified histone sites impaired MLV but not HIV-1 integration in infected cells. Comparison of the distribution of BET protein-binding sites analyzed using ChIP-Seq data and MLV-integration sites revealed significant positive correlations. Antagonism of BET proteins, via JQ-1 treatment or RNA interference, reduced MLV-integration frequencies at transcription start sites. These findings elucidate the importance of BET proteins for MLV integration efficiency and targeting and provide a route to developing safer MLV-based vectors for human gene therapy. (1-4). The selection of chromosomal targets for retroviral integration varies markedly, tracking with the genus of the retrovirus studied (5-7). For example, the γ-retroviruses favor integration near transcription start sites, whereas lentiviruses favor integration within transcription units. These observations have suggested that different cellularbinding partners of retroviral integrases are likely to be responsible for integration target-site selection. However, to date, only one example has been reported: lens epithelium-derived growth factor (LEDGF/p75), which functions as a bimodal tether that engages HIV-1 intasomes and navigates them to active genes (8-14). Cellular cofactors of other retroviral genera are currently unknown.The molecular mechanisms of γ-retroviral murine leukemia virus (MLV) integration are of particular significance because MLV-based vectors are used for human gene therapy. In clinical trials, the use of γ-retroviral vectors to correct primary immunodeficiencies has been curative, but adverse events have occurred associated with insertion of MLV-based vectors near protooncogenes (reviewed in refs. 15-18). The identification of cellular factors for γ-retroviruses may provide mechanistic clues to facilitate the development of safer gene-therapy vectors.In this report, we have identified the bromodomain and extraterminal domain (BET) proteins (Brd2, -3, -4) as the cellularbinding partners of MLV IN and demonstrate their significance for stimulating and targeting MLV integration at transcription start sites. (Table 1, Table S1, and Fig. S1). Of these, Brd4 and Brd3 were the top hits in NIH 3T3 and Sup-T1 cells, respectively. Differential pull-down levels of these proteins (Table 1) could be attributable to the varying expression le...

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“…Brd4 binds acetylated histones and is associated with chromatin throughout mitosis (10,11). Brd4 colocalizes with E2 in distinct speckles on mitotic chromosomes (7), and disruption of this interaction dissociates E2 from chromosomes (8). Thus, the E2-Brd4 association is crucial for BPV1 episomal genome segregation.…”

mentioning

confidence: 99%

“…Shorter E2 repressor proteins, which contain only the DNA binding͞ dimerization domain, antagonize the functions of the full-length protein and are unable to associate with mitotic chromosomes. The cellular bromodomain protein Brd4 is important for the association of the BPV1 E2 protein and viral genomes with mitotic chromosomes (7)(8)(9). Brd4 binds acetylated histones and is associated with chromatin throughout mitosis (10,11).…”

mentioning

confidence: 99%

Variations in the association of papillomavirus E2 proteins with mitotic chromosomes

Oliveira

Colf

McBride

2006

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

Self Cite

100

145

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The E2 protein segregates episomal bovine papillomavirus (BPV) genomes to daughter cells by tethering them to mitotic chromosomes, thus ensuring equal distribution and retention of viral DNA. To date, only the BPV1 E2 protein has been shown to bind to mitotic chromosomes. We assessed the localization of 13 different animal and human E2 proteins from seven papillomavirus genera, and we show that most of them are stably bound to chromosomes throughout mitosis. Furthermore, in contrast to the random association of BPV1 E2 with mitotic chromosomes, several of these proteins appear to bind to more specific regions of mitotic chromosomes. Using human papillomavirus (HPV) type 8 E2, we show that this region is adjacent to centromeres͞kinetochores. Therefore, E2 proteins from both HPV and animal papillomavirus bind to mitotic chromosomes, and there are variations in the specificity of this binding. Only the ␣-papillomavirus E2 proteins do not stably associate with mitotic chromatin throughout mitosis. These proteins closely associate with prophase chromosomes and bind to chromosomes in telophase but not in metaphase. However, extraction of mitotic cells before fixation results in ␣-E2 proteins binding to the pericentromeric region of metaphase chromosomes, as observed for HPV8 E2. We postulate that this is the authentic target of these E2 proteins but that additional factors or a specialized cellular environment is required to stabilize this association. Thus, E2-mediated tethering of viral genomes to mitotic chromosomes is a common strategy of papillomaviruses, but different viruses have evolved different variations of this theme.human papillomavirus ͉ mitosis ͉ replication ͉ segregation T here are 17 distinct genera of Papillomaviridae (1); each virus infects a specific region of cutaneous or mucosal epithelium in a particular host. For example, human papillomavirus (HPV) types 1, 2, 3, and 4 cause plantar and palmar warts whereas HPV5 and HPV8 are found in cutaneous lesions of epidermodysplasia verruciformis. Mucosal HPV types such as HPV6, HPV11, HPV16, and HPV31 infect genital and sometimes oral epithelia. These infections are usually persistent, and so papillomaviruses need a mechanism to efficiently retain the extrachromosomal genomes within dividing cells.The viral E1 and E2 proteins initiate viral DNA replication by binding to the replication origin. Multiple E2 binding sites are required in addition for the genome to be stably maintained in dividing cells (2). The bovine papillomavirus (BPV) type 1 E2 protein tethers the genomes by means of the E2 binding sites to cellular mitotic chromosomes (3-5) to ensure that they are retained in the nucleus and distributed to daughter cells. This mechanism is a common one in persistent episomal viruses; Epstein-Barr virus and human herpesvirus 8 also each encode a protein that tethers the viral genomes to mitotic chromosomes to ensure their faithful segregation.The E2 protein is also a transcriptional regulator, consisting of a transactivation domain and a dimerization͞DN...

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Interaction of Bovine Papillomavirus E2 Protein with Brd4 Stabilizes Its Association with Chromatin

Cited by 99 publications

References 60 publications

Brd4 links chromatin targeting to HPV transcriptional silencing

Brd4 links chromatin targeting to HPV transcriptional silencing

BET proteins promote efficient murine leukemia virus integration at transcription start sites

Variations in the association of papillomavirus E2 proteins with mitotic chromosomes

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