Maintenance of Human Papillomavirus Genomes

人乳头瘤病毒基因组的维护

• 批准号: 7280372
• 负责人: Peter C. Angeletti
• 金额: $ 14.21万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7280372
• 关键词: Binding; Binding Sites; Bos taurus; Bovine Papillomavirus; Cattle; Cells; Chromosomes, Human, Pair 6; Coupled; Cultured Cells; DNA; DNA Damage; Elements; Generations; Genome; Genome Stability; Genomics; Goals; HPV-High Risk; Human; Human Papillomavirus; Human papillomavirus 16; Indium; Invasive; Life Cycle Stages; Link; Maintenance; Malignant neoplasm of cervix uteri; Maps; Mediating; Mitotic Chromosome; Nuclear; Numbers; Oncogenic Viruses; Papillomavirus; Plasmids; Play; Property; Proteins; Recruitment Activity; Regulator Genes; Replication Origin; Risk; Role; Signal Transduction; Stratified Squamous Epithelium; Stratum Basale; System; Testing; Transcriptional Regulation; Translations; Viral; Viral Genome; Virus; Yeasts; base; cis acting element; daughter cell; helicase; keratinocyte; mutant; novel; research study; segregation

DESCRIPTION (provided by applicant): High-risk anogenital papillomaviruses (HPVs) are associated with 95% of invasive cervical cancers worldwide. These viruses infect and replicate in stratified squamous epithelia, where they can persist for long periods. The double-stranded circular HPV genomic DNA is maintained as a low-copy-number nuclear plasmid in the mitotically active basal layer keratinocytes. Trans-acting viral factors E1 and E2 play an important role in replication; El, a helicase, recruits Polalpha to the origin; E2 acts cooperatively by binding E1 and the viral genome through its binding sites. Studies of bovine papillomavirus type 1 (BPV-1) suggest that E2 mediates segregation of newly synthesized viral genomes to daughter cells by linking them to mitotic chromosomes. We have recently developed a yeast-based system to study the cis and trans requirements for HPV16 replication and maintenance. Experiments performed in this system and in human cells indicate that E2 may not be strictly required for long-term maintenance of HPV16 genomes. This result suggests that the cis and trans requirements for extrachromosomal maintenance of HPV16 need to be further evaluated. The objectives of this proposal are: (1) To investigate the role of E2 in HPV16 maintenance; (2) To map cis-acting elements in the HPV16 genome that provide maintenance functions independently of E2; and (3) To identify cellular factors that contribute to genome maintenance. These studies will clarify the mechanism by which these oncogenic viruses maintain their genomes in the host.

描述（由申请人提供）： 高危肛门生殖器乳头状瘤病毒（HPV）与全球95%的浸润性宫颈癌相关。 这些病毒在复层鳞状上皮中感染和复制，在那里它们可以持续很长时间。 双链环状HPV基因组DNA在有丝分裂活跃的基底层角质形成细胞中保持为低拷贝数的核质粒。 反式作用病毒因子E1和E2在复制中起重要作用; E1是一种解旋酶，将Polalpha募集到起点; E2通过其结合位点将E1与病毒基因组结合而协同作用。 对牛乳头瘤病毒1型（BPV-1）的研究表明，E2通过将新合成的病毒基因组连接到有丝分裂染色体上，介导病毒基因组向子细胞的分离。 我们最近开发了一种基于酵母的系统来研究HPV 16复制和维持的顺式和反式要求。 在该系统和人类细胞中进行的实验表明，E2可能不是HPV 16基因组长期维持所严格需要的。 这一结果表明，HPV 16的染色体外维持的顺式和反式需要进一步评估。 本研究的目的是：（1）研究E2在HPV 16维持中的作用;（2）定位HPV 16基因组中独立于E2提供维持功能的顺式作用元件;（3）鉴定有助于基因组维持的细胞因子。 这些研究将阐明这些致癌病毒在宿主体内维持其基因组的机制。