Chromatin structure maintenance and cancer

描述(申请人提供)：染色质结构组织对调节许多基本的细胞过程至关重要。染色质结构的紊乱与包括癌症在内的许多人类遗传病有关。然而，调控高阶染色质结构组装的分子机制仍然知之甚少。我们以前的工作确定细胞蛋白Brd4(溴域包含蛋白4)是宫颈癌相关乳头状瘤病毒的一种新的染色质受体。BRD4在细胞周期调控和癌症中发挥重要作用。我们的功能研究已经确定了Brd4在染色质结构维持中的作用。BRD4也是致癌的卡波西肉瘤相关疱疹病毒(KSHV)和定义高致命性癌症的t(15；19)基因易位的靶点。我们推测，Brd4细胞在染色质结构维持中功能的丧失是致瘤病毒和易位相关癌的致癌机制的基础。我们的研究将应用最近发展的随机光学重建显微镜(STORM)技术和原位单细胞成像技术来进一步研究Brd4在染色质结构组织中的功能。我们将研究Brd4介导染色质结构维持的机制。利用与癌症相关的病毒蛋白和基因突变作为分子探针，我们将进一步探索这些致癌因子通过取消Brd4功能来促进恶性进展的机制。这些综合研究将使我们更好地了解Brd4在高阶染色质组织和癌症中的作用。这项研究将为研究其他含溴结构域染色质接头的分子机制提供一个范例。这项研究的结果将为开发有效的抗癌治疗策略提供有希望的线索。 公共卫生相关性：我们之前已经确定溴结构域蛋白Brd4是人类乳头瘤病毒的宿主受体，而人类乳头瘤病毒与宫颈癌密切相关。在这项资助中，我们建议研究Brd4在染色质结构维持中潜在的分子机制。我们将确定肿瘤病毒和基因突变导致Brd4细胞功能丧失如何导致人类癌症。这项研究将为开发有效的抗癌治疗策略提供新的见解。

DESCRIPTION (provided by applicant): 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.