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（由申请人提供）：默克尔细胞多瘤病毒（MCV）是一种新型人多瘤病毒，最近在默克尔细胞癌（MCC）（一种高致死性皮肤癌）中发现。过度暴露于紫外线（UV）辐射和免疫抑制是MCV相关癌症的最重要风险因素。MCC转移迅速。它是最具侵袭性的人类皮肤癌之一，死亡率高达33%，超过黑色素瘤的死亡率，五年生存率低于45%。MCC的发病率在过去的20年中增加了两倍，因为人口老龄化和长期暴露在阳光下的增加。虽然MCV是人类皮肤上大量存在的病毒，但对病毒生命周期的许多方面仍知之甚少。目前还不清楚MCV感染如何改变皮肤生理学，导致高度侵袭性的MCC。随着MCV感染的高流行率和MCC诊断量的增加，需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Brd 4与MCV大T抗原（LT）相互作用并募集细胞复制因子RFC以支持病毒DNA复制。这项研究提供了第一个深入了解MCV复制机制。我们进一步证明，在MCV感染期间，病毒激活并招募宿主DNA损伤反应（DDR）因子以支持病毒DNA复制。此外，MCV LT C-末端DNA结合和解旋酶区域也引起宿主基因组中的DNA损伤以诱导DDR并激活p53，从而导致细胞增殖的抑制。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关键事件。基于这些新发现，我们假设MCV劫持细胞DNA修复系统，以帮助其自身的复制和入侵MCV基因组和宿主DNA修复机制之间的相互作用冲突的失调，可导致基因组不稳定和癌症。我们将使用我们实验室建立的一些创新技术来阐明MCV的生命周期和自然感染细胞中的宿主DNA修复，以确定宿主DDR因子促进MCV复制的机制，并研究阳光暴露/UV辐射如何促进MCV诱导的致癌进展。通过这些综合研究，我们的目标是提供对MCV生命周期和致癌机制的更深入了解，并为开发有效的治疗策略以治愈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自己在MCV研究的专业知识，以及我们在UPENN社区建立的皮肤病研究的合作和资源。