BRD4 Phosphorylation Regulates HPV E2-Mediated Viral Transcription, Origin Replication, and Cellular MMP-9 Expression

Wu, Shwu-Yuan; Nin, Dawn Sijin; Lee, A‐Young; Simanski, Scott; Kodadek, Thomas; Chiang, Cheng-Ming

doi:10.1016/j.celrep.2016.07.001

Cited by 78 publications

(125 citation statements)

References 34 publications

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“…3D). Thus, Y102E is unable to interact with the established E2-binding CTM of Brd4 but can bind in vitro to the BID region, which is known to be mediated by the E2 C-terminal DNA-binding domain (DBD) (40).…”

Section: Resultsmentioning

confidence: 99%

“…3C). It was recently reported that distinct domains in Brd4 undergo conformational changes to interact with p53 (39) and HPV E2 (40). We tested the basic residue-enriched interaction domain (BID) for an association with BPV-1 E2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The BID binds to p53 (39) and was recently shown to interact with the PV E2 DNA-binding domain (40). In Brd4:p53 interaction studies, BID was found to undergo a conformational change induced by serine phosphorylation within a different Brd4 region termed the phosphorylationdependent interaction domain (PDID) (39).…”

Section: Discussionmentioning

confidence: 99%

“…High-risk HPVs bind to phospho-PDID, CTM, and BID regions, whereas low-risk HPVs and BPV bind only to the CTM and BID regions of Brd4. While BPV E2 could potentially bind to the Brd4 BID, this interaction is normally undetectable in vivo, as the BID is usually masked by its intramolecular contact with the phospho-PDID and is thus unavailable for interactions with BPV-1 E2 (40).…”

Section: Discussionmentioning

confidence: 99%

“…In Brd4:p53 interaction studies, BID was found to undergo a conformational change induced by serine phosphorylation within a different Brd4 region termed the phosphorylationdependent interaction domain (PDID) (39). Similarly, Brd4 uses a phosphorylation switch within the PDID to modulate binding between high-risk HPV and low-risk HPV (40). High-risk HPVs bind to phospho-PDID, CTM, and BID regions, whereas low-risk HPVs and BPV bind only to the CTM and BID regions of Brd4.…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of the Bovine Papillomavirus E2 Protein on Tyrosine Regulates Its Transcription and Replication Functions

Culleton

Kanginakudru

DeSmet

et al. 2017

J Virol

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Papillomaviruses are small, double-stranded DNA viruses that encode the E2 protein, which controls transcription, replication, and genome maintenance in infected cells. Posttranslational modifications (PTMs) affecting E2 function and stability have been demonstrated for multiple types of papillomaviruses. Here we describe the first phosphorylation event involving a conserved tyrosine (Y) in the bovine papillomavirus 1 (BPV-1) E2 protein at amino acid 102. While its phosphodeficient phenylalanine (F) mutant activated both transcription and replication in luciferase reporter assays, a mutant that may act as a phosphomimetic, with a Y102-toglutamate (E) mutation, lost both activities. The E2 Y102F protein interacted with cellular E2-binding factors and the viral helicase E1; however, in contrast, the Y102E mutant associated with only a subset and was unable to bind to E1. While the Y102F mutant fully supported transient viral DNA replication, BPV genomes encoding this mutation as well as Y102E were not maintained as stable episomes in murine C127 cells. These data imply that phosphorylation at Y102 disrupts the helical fold of the N-terminal region of E2 and its interaction with key cellular and viral proteins. We hypothesize that the resulting inhibition of viral transcription and replication in basal epithelial cells prevents the development of a lytic infection.IMPORTANCE Papillomaviruses (PVs) are small, double-stranded DNA viruses that are responsible for cervical, oropharyngeal, and various genitourinary cancers. Although vaccines against the major oncogenic human PVs are available, there is no effective treatment for existing infections. One approach to better understand the viral replicative cycle, and potential therapies to target it, is to examine the posttranslational modification of viral proteins and its effect on function. Here we have discovered that the bovine papillomavirus 1 (BPV-1) transcription and replication regulator E2 is phosphorylated at residue Y102. While a phosphodeficient mutant at this site was fully functional, a phosphomimetic mutant displayed impaired transcription and replication activity as well as a lack of an association with certain E2-binding proteins. This study highlights the influence of posttranslational modifications on viral protein function and provides additional insight into the complex interplay between papillomaviruses and their hosts.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Phosphorylation of the Bovine Papillomavirus E2 Protein on Tyrosine Regulates Its Transcription and Replication Functions

Culleton

Kanginakudru

DeSmet

et al. 2017

J Virol

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BRD4 as a potential target for human papillomaviruses associated cancer

Rani,

Bonam,

Zhou

et al. 2023

Journal of Medical Virology

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Around 99% of cervical cancer and 5%–10% of human cancer are associated with human papillomaviruses (HPV). Notably, the life‐cycle of HPV begins by low‐level infection of the basal cells of the stratified epithelium, where the viral genomes are replicated and passed on to the daughter proliferating basal cells. The production of new viral particles remains restricted to eventually differentiated cells. HPVs support their persistent infectious cycle by hijacking pivotal pathways and cellular processes. Bromodomain‐containing protein 4 (BRD4) is one of the essential cellular factors involved in multiple stages of viral transcription and replication. In this review, we demonstrate the role of BRD4 in the multiple stages of HPV infectious cycle. Also, we provide an overview of the intense research about the cellular functions of BRD4, the mechanism of action of bromodomain and extra terminal inhibitors, and how it could lead to the development of antiviral/anticancer therapies.

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Recent progress and structural analyses of domain‐selective BET inhibitors

Divakaran

Harki

Pomerantz

2023

Medicinal Research Reviews

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Epigenetic mechanisms for controlling gene expression through heritable modifications to DNA, RNA, and proteins, are essential processes in maintaining cellular homeostasis. As a result of their central role in human diseases, the proteins responsible for adding, removing, or recognizing epigenetic modifications have emerged as viable drug targets. In the case of lysine‐ε‐N‐acetylation (Kac), bromodomains serve as recognition modules (“readers”) of this activating epigenetic mark and competition of the bromodomain‐Kac interaction with small‐molecule inhibitors is an attractive strategy to control aberrant bromodomain‐mediated gene expression. The bromodomain and extra‐terminal (BET) family proteins contain eight similar bromodomains. These BET bromodomains are among the more commonly studied bromodomain classes with numerous pan‐BET inhibitors showing promising anticancer and anti‐inflammatory efficacy. However, these results have yet to translate into Food and Drug Administration‐approved drugs, in part due to a high degree of on‐target toxicities associated with pan‐BET inhibition. Improved selectivity within the BET‐family has been proposed to alleviate these concerns. In this review, we analyze the reported BET‐domain selective inhibitors from a structural perspective. We highlight three essential characteristics of the reported molecules in generating domain selectivity, binding affinity, and mimicking Kac molecular recognition. In several cases, we provide insight into the design of molecules with improved specificity for individual BET‐bromodomains. This review provides a perspective on the current state of the field as this exciting class of inhibitors continue to be evaluated in the clinic.

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BRD4 Phosphorylation Regulates HPV E2-Mediated Viral Transcription, Origin Replication, and Cellular MMP-9 Expression

Cited by 78 publications

References 34 publications

Phosphorylation of the Bovine Papillomavirus E2 Protein on Tyrosine Regulates Its Transcription and Replication Functions

Phosphorylation of the Bovine Papillomavirus E2 Protein on Tyrosine Regulates Its Transcription and Replication Functions

BRD4 as a potential target for human papillomaviruses associated cancer

Recent progress and structural analyses of domain‐selective BET inhibitors

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