Chromatin structure organization is crucial for regulating many fundamental cellular processes. Perturbations of chromatin structure have been linked to many human genetic diseases including cancer. However the molecular mechanism that regulates the assembly of higher-order chromatin structure remains poorly understood. Our previous work identified the cellular protein Brd4 (bromodomain-containing protein 4) as a novel chromatin receptor for cervical cancer-associated papillomaviruses. Brd4 plays an important role in cell cycle regulation and cancer. Our functional studies have established the Brd4 function in chromatin structure maintenance. Brd4 is also a target of the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), and the genetic translocation t(15;19) that defines a highly lethal carcinoma. We hypothesize that abrogation of the Brd4 cellular function in chromatin structure maintenance underlies the oncogenic mechanisms for the tumorigenic viruses- and translocation-associated carcinoma. Our proposed studies will apply recently developed Stochastic Optical Reconstruction Microscopy (STORM) technology and in situ single cell imaging to further examine Brd4 function in chromatin structure organization. We will investigate the mechanisms by which Brd4 mediates the chromatin structure maintenance. Using the cancer-associated viral proteins and genetic mutations as molecular probes, we will further explore the mechanisms by which these oncogenic agents abrogate the Brd4 function to contribute to malignant progression. These integrated studies will provide greater understanding of the Brd4 function in higher-order chromatin organization and cancer. This study will present a paradigm for investigating the molecular mechanisms of other bromodomain- containing chromatin adaptors. The outcome of this study will offer promising leads for developing efficient anti-cancer therapeutic strategies.

Public Health Relevance

We have previously identified the bromodomain protein Brd4 as a host receptor for human papillomaviruses that are strongly associated with cervical cancer. In this grant, we propose to investigate the molecular mechanisms underlying the Brd4 function in chromatin structure maintenance. We will determine how abrogation of Brd4 cellular function by tumor viruses and genetic mutation could cause human cancers. This study will provide new insights for developing efficient anti-cancer therapeutic strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Okano, Paul
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University of Pennsylvania
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Krump, Nathan A; Liu, Wei; You, Jianxin (2018) Mechanisms of persistence by small DNA tumor viruses. Curr Opin Virol 32:71-79
Liu, Wei; Krump, Nathan A; MacDonald, Margo et al. (2018) Merkel Cell Polyomavirus Infection of Animal Dermal Fibroblasts. J Virol 92:
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Wang, Ranran; You, Jianxin (2015) Mechanistic analysis of the role of bromodomain-containing protein 4 (BRD4) in BRD4-NUT oncoprotein-induced transcriptional activation. J Biol Chem 290:2744-58
Li, Jing; Diaz, Jason; Wang, Xin et al. (2015) Phosphorylation of Merkel cell polyomavirus large tumor antigen at serine 816 by ATM kinase induces apoptosis in host cells. J Biol Chem 290:1874-84

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