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)是一种新的人类多瘤病毒，最近在高度致命的皮肤癌默克尔细胞癌(MCC)中发现。过度暴露于紫外线辐射和免疫抑制是MCV相关癌症的最重要的危险因素。MCC转移速度很快。它是人类最具侵袭性的皮肤癌之一，死亡率极高，达33%，超过黑色素瘤的比率，五年生存率不到45%。在过去的20年里，随着长期暴露在阳光下的老龄化人口的增加，MCC的发病率增加了两倍。虽然MCV是一种在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。MCV感染如何改变皮肤生理从而导致高度侵袭性的MCC也不清楚。随着MCV感染的高流行率和MCC诊断量的增加，有必要更好地了解这种病毒及其致癌潜力。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。这项研究提供了对MCV复制机制的第一次洞察。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)因子来支持病毒DNA复制。此外，MCV LT的C末端DNA结合和解旋酶区域也会导致宿主基因组中的DNA损伤，从而诱导DDR并激活P53，从而抑制细胞增殖。我们的研究解释了为什么在MCV诱导的肿瘤发生过程中，LT C-末端区域的缺失是一个关键事件。在这些新发现的基础上，我们假设MCV劫持细胞DNA修复系统以帮助自己复制和失调入侵的MCV基因组和宿主DNA修复机制之间的冲突相互作用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一些创新技术来阐明MCV在自然感染细胞中的生命周期和宿主DNA修复，确定宿主DDR因子促进MCV复制的机制，并研究阳光暴露/紫外线辐射如何促进MCV诱导的肿瘤进展。通过这些综合研究，我们的目标是更好地了解MCV的生命周期和致癌机制，并为开发有效的治疗策略来治疗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，并将从我们自己在MCV研究方面的专业知识以及我们在宾夕法尼亚大学社区建立的皮肤病研究合作和资源中受益匪浅。