Genetic and Biochemical Studies of the KSHV LANA Gene

KSHV LANA 基因的遗传和生化研究

• 批准号: 8015635
• 负责人: Kenneth M Kaye
• 金额: $ 38.56万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015635
• 关键词: Acquired Immunodeficiency Syndrome; Address; Amino Acids; Area; Binding; Biochemical; Biology; C-terminal; Cell Nucleus; Cells; Chromosomes; Clinical; DNA; DNA Binding; DNA biosynthesis; Daughter; Development; Disease; Episome; Future; Genes; Genetic; Herpesviridae; Herpesviridae Infections; Histone H2A; Human; Human Herpesvirus 8; Immune response; Investigation; Kaposi Sarcoma; Knowledge; Lead; Light; Link; Lymphoma; Lytic; Maintenance; Malignant Neoplasms; Mediating; Mitotic Chromosome; Multicentric Angiofollicular Lymphoid Hyperplasia; N-terminal; Patients; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerases; Preventive; Process; Proliferating; Proteins; Risk; Role; Terminal Repeat Sequences; Therapeutic; Viral; Virus Latency; Work; antigen binding; effusion; inhibitor/antagonist; insight; latency-associated nuclear antigen; latent infection; neoplastic cell; novel; novel therapeutics; prevent; public health relevance; response; segregation; small molecule; tool; tumor; viral DNA

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is etiologically linked with KS, primary effusion lymphomas (PELs) and multicentric Castleman's disease. These diseases occur in AIDS and in other patients and current therapies are limited. KSHV latently infects the vast majority of tumor cells and viral DNA persists as a multiple copy, extrachromosomal, circular episome. To persist in proliferating cells, episomes must replicate and efficiently segregate to daughter nuclei. KSHV latency associated nuclear antigen (LANA) binds terminal repeat (TR) DNA to mediate KSHV episome persistence. LANA mediates TR DNA replication and binds TR DNA to tether episomes to mitotic chromosomes for efficient segregation to progeny nuclei. LANA is essential for KSHV episome maintenance and central to viral latency. The N- and C-terminal regions are essential for LANA function and bind mitotic chromosomes and TR DNA. However, the role(s) of internal domains in LANA mediated episome maintenance are unknown. We have now identified a 68 amino acid internal LANA region which exerts a critical effect on episome maintenance. We have also found that poly(ADP-ribose) polymerase-1 (PARP1) exerts a potent inhibitory effect on LANA mediated episome persistence. Small molecule inhibitors of LANA function would be powerful tools to probe LANA function and viral latency and would provide new therapeutic strategies. However, currently, no such inhibitors have been identified or developed. This work will address critical aspects of LANA biology. The newly identified internal LANA region critical for episome maintenance will be investigated, including its mechanism of action. Such knowledge will provide insight into the basic mechanisms of LANA mediated episome persistence. The biology of PARP1 inhibition of episome maintenance will be investigated. Study of this area is critical since PARP1 appears to be a key component of the host response to KSHV infection. Small molecule inhibitors of LANA function will be identified. These compounds will provide novel probes of KSHV latency and serve as potential therapeutic and preventive agents for KSHV malignancy. PUBLIC HEALTH RELEVANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) has a causative role in several human malignancies. KSHV infects and persists in tumor cells. This work investigates the mechanisms by which KSHV is able to persist and survive in the tumor cells. A better understanding of this viral persistence may allow development of strategies which prevent or treat KSHV tumors.

描述（由申请人提供）：Kaposi的肉瘤（KS）相关疱疹病毒（KSHV）在病因上与KS，一级积液淋巴瘤（PELS）和多中心Castleman病有关。这些疾病发生在艾滋病和其他患者中，目前的疗法受到限制。 KSHV潜在地感染了绝大多数肿瘤细胞，病毒DNA一直持续为多拷贝，即外肌体，圆形综合体。为了持续增殖细胞，插发体必须复制并有效地隔离到子核。 KSHV潜伏期相关的核抗原（LANA）结合末端重复（TR）DNA以介导KSHV偶发效应。 LANA介导TR DNA复制，并将TR DNA与链醚偶发结合到有丝分裂染色体，以有效地分离到后代核。 LANA对于KSHV ISSOIMOME维护至关重要，并且对病毒潜伏期至关重要。 N-和C末端区域对于LANA功能至关重要，并结合有丝分裂染色体和TR DNA。然而，内部域在LANA介导的沿着沿着沿着的综合体维持中的作用尚不清楚。现在，我们已经确定了一个68个氨基酸内部LANA区域，该区域对沿着情节群维护产生关键影响。我们还发现，聚（ADP-核糖）聚合酶1（PARP1）对LANA介导的偶发持续性产生有效的抑制作用。 LANA功能的小分子抑制剂将是探测LANA功能和病毒潜伏期的强大工具，并提供新的治疗策略。但是，目前尚未确定或开发此类抑制剂。 这项工作将解决LANA生物学的关键方面。新确定的内部LANA区域将研究至关重要的维护，包括其作用机理。这种知识将洞悉LANA介导的围绕次数持久性的基本机制。将研究PARP1抑制的生物学生物学。对该区域的研究至关重要，因为PARP1似乎是宿主对KSHV感染反应的关键组成部分。将确定LANA功能的小分子抑制剂。这些化合物将提供新颖的KSHV潜伏期探针，并作为KSHV恶性肿瘤的潜在治疗和预防剂。 公共卫生相关性：Kaposi的肉瘤相关疱疹病毒（KSHV）在几种人类恶性肿瘤中起着致命的作用。 KSHV在肿瘤细胞中感染并持续。这项工作调查了KSHV能够在肿瘤细胞中持续和生存的机制。更好地了解这种病毒持久性可以允许制定预防或治疗KSHV肿瘤的策略。