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; 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（由适用提供）：默克尔细胞多瘤病毒（MCV）是一种新型的人类多瘤病毒，最近在一种高度致命的皮肤癌中发现了默克尔细胞癌（MCC）。过度暴露于紫外线（UV）辐射和免疫抑制是MCV相关癌症的最重要危险因素。 MCC迅速转移。它是最具侵略性的人类皮肤癌之一，其死亡率极高的33％超过黑色素瘤率，五年生存率小于45％。在过去的20年中，随着人口的衰老人数延长，MCC的事件增加了两倍。尽管MCV是人类皮肤上的丰富病毒，但病毒生命周期的许多方面仍然了解不足。目前尚不清楚MCV感染如何改变皮肤生理，从而引起高度侵略性的MCC。随着MCV感染的高患病率和MCC诊断量的增加，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，并募集细胞复制因子RFC以支持病毒DNA复制。 TH研究提供了对MCV复制机制的第一个见解。我们进一步证明，在MCV感染期间，病毒激活并募集宿主DNA损伤反应（DDR）因子以支持病毒DNA复制。此外，MCV LT C末端DNA结合和解旋酶区域还会导致宿主基因组中的DNA损伤诱导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引起的肿瘤发生过程中的关键事件。在这些新发现的基础上，我们假设MCV劫持了细胞DNA修复系统，以帮助其自身的复制和失调，使入侵的MCV基因组与宿主DNA修复机械之间的冲突相互作用可能导致基因组不稳定性和癌症。我们将使用实验室中建立的许多创新技术来阐明自然感染细胞中的MCV生命周期和宿主DNA修复，以确定宿主DDR因子有助于MCV复制的机制，并研究阳光暴露/UV辐射如何促进MCV诱导的MCV诱导的Oncenic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多了解，并为制定有效的治疗策略提供有望的潜在客户来治愈MCV感染和相关的癌症。这些研究将是可行的，并且将从我们自己在MCV研究方面的专业知识以及我们在Upenn社区中建立的皮肤病研究的合作和资源中受益匪浅。