Merkel cell polyomavirus infection, DNA damage response and cancer

默克尔细胞多瘤病毒感染、DNA 损伤反应与癌症

• 批准号: 9016508
• 负责人: Jianxin You
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9016508
• 关键词: Affect; Applications Grants; C-terminal; Calcium; Cell Proliferation; Cells; Collaborations; Communities; Complement; Complex; Conflict (Psychology); DNA; DNA Binding; DNA Damage; DNA Repair; DNA biosynthesis; Development; Diagnosis; Elderly; Epithelial; Equilibrium; Event; Exposure to; Gene Expression; Genetic Transcription; Genome; Genomic Instability; Goals; Grant; Health; High Prevalence; Human; Impairment; In Situ Hybridization; Incidence; Invaded; Ionizing radiation; Large T Antigen; Lead; Learning; Life Cycle Stages; Lung; Malignant Neoplasms; Mediating; Merkel Cells; Merkel cell carcinoma; Methylcellulose; Molecular; Mutation; Neoplasm Metastasis; Oncogenic; Oncogenic Viruses; Polyomavirus; Polyomavirus Infections; Polyomaviruses Large T Proteins; Process; Proteins; Recruitment Activity; Reporting; Research; Resources; Risk Factors; Role; Skin; Skin Cancer; Skin Physiology; Staining method; Stains; Sun Exposure; Survival Rate; System; TP53 gene; Techniques; Therapeutic; Time; UV Radiation Exposure; Ultraviolet Rays; Undifferentiated; Viral; Viral Genome; Virion; Virus; Virus Replication; aging population; genome integrity; helicase; in vivo; innovation; insight; keratinocyte; melanoma; mortality; novel; radiation immunosuppression; research study; response; skin disorder; tool; tumor; tumorigenesis; ultraviolet; viral DNA; virus host interaction

 DESCRIPTION (provided by applicant): Merkel cell polyomavirus (MCV) is a novel human polyomavirus that has recently been discovered in Merkel cell carcinoma (MCC), a highly lethal skin cancer. Excessive exposure to ultraviolet (UV) radiation and immunosuppression are the most important risk factors for MCV-associated cancers. MCC metastasizes rapidly. It is one of the most aggressive human skin cancers with an extremely high mortality rate of 33% exceeding the rate of melanoma and less than 45% five-year survival rate. The incidence of MCC has tripled over the past 20 years as the aging population with prolonged sun exposure increases. Although MCV is an abundant virus on human skin, many aspects of the viral life cycle remain poorly understood. It is also unclear how MCV infection changes skin physiology to cause the highly aggressive MCC. With the high prevalence of MCV infection and the increasing amount of MCC diagnosis, there is a need to better understand the virus and its oncogenic potential. Recently, we discovered that the host protein Brd4 interacts with the MCV large T antigen (LT) and recruits the cellular replication factor RFC to support viral DNA replication. Thi study provides the first insight into the MCV replication machinery. We further demonstrated that, during MCV infection, the virus activates and recruits host DNA damage response (DDR) factors to support viral DNA replication. In addition, the MCV LT C-terminal DNA binding and helicase region also causes DNA damage in the host genome to induce DDR and activate p53, leading to inhibition of cellular proliferation. Our study explains why deletion of the LT C-terminl region is a critical event during MCV-induced oncogenesis. Building on these new discoveries, we hypothesize that MCV hijacks the cellular DNA repair systems to aid its own replication and dysregulation of the conflicting interactions between the invading MCV genomes and the host DNA repair machinery can result in genomic instability and cancer. We will use a number of innovative techniques established in our lab to elucidate the MCV life cycle and host DNA repair in naturally infected cells, to determine the mechanisms by which host DDR factors contributes to MCV replication, and to investigate how sunlight exposure/UV radiation promotes MCV-induced oncogenic progression. Through these integrated studies, our goal is to provide greater understanding of the MCV life cycle and oncogenic mechanism, and offer promising leads for developing effective therapeutic strategies to cure MCV infection and associated cancers. These studies will be feasible, and will benefit greatly from our own expertise in MCV research as well as from the collaborations and resources for skin disease research that we have established in the UPENN community.

 描述（申请人提供）：默克尔细胞多瘤病毒（MCV）是一种新型人类多瘤病毒，最近在默克尔细胞癌（MCC）中发现，默克尔细胞癌是一种高度致命的皮肤癌，过度暴露于紫外线（UV）辐射和免疫抑制是最致命的。 MCV 相关癌症的重要危险因素 MCC 是最具侵袭性的人类皮肤癌之一，死亡率极高，超过 33%。黑色素瘤和低于 45% 的五年生存率随着人口老龄化和长期阳光照射的增加，MCC 的发病率在过去 20 年中增加了两倍。目前尚不清楚 MCV 感染如何改变皮肤生理学从而导致高度侵袭性 MCC。随着 MCV 感染的高患病率和 MCC 诊断数量的增加，有必要更好地了解该病毒及其致癌潜力。最近，我们发现宿主蛋白 Brd4 与 MCV 大 T 抗原 (LT) 相互作用，并招募细胞复制因子 RFC 来支持病毒 DNA 复制。我们进一步证明，在 MCV 感染期间，宿主蛋白 Brd4 能够与 MCV 大 T 抗原 (LT) 相互作用。 ，病毒激活并招募宿主DNA损伤反应（DDR）因子来支持病毒DNA复制，此外，MCV LT C末端DNA结合和解旋酶区域也会引起宿主基因组中的DNA损伤，从而诱导DDR并激活p53，我们的研究解释了为什么 LT C 末端区域的缺失是 MCV 诱导的肿瘤发生过程中的一个关键事件。基于这些新发现，我们发现 MCV 劫持了细胞 DNA 修复系统以帮助其自身复制。入侵的 MCV 基因组和宿主 DNA 修复机制之间的冲突相互作用的失调可能导致基因组不稳定和癌症。我们将使用我们实验室建立的许多创新技术来阐明 MCV 生命周期和宿主 DNA 修复。在自然感染的细胞中，确定宿主 DDR 因子促进 MCV 复制的机制，并研究阳光照射/紫外线辐射如何促进 MCV 诱导的致癌进展。通过这些综合研究，我们的目标是更好地了解 MCV。生命周期和致癌机制，并为开发有效的治疗策略来治愈 MCV 感染和相关癌症提供有希望的线索。这些研究将是可行的，并将大大受益于我们在 MCV 研究方面的专业知识以及皮肤领域的合作和资源。我们的疾病研究已在 UPENN 社区建立。