Suppression of mobile elements by p53 genes

p53 基因对移动元件的抑制

• 批准号: 10308726
• 负责人: John M Abrams
• 金额: $ 34.44万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308726
• 关键词: Acute; Address; Alleles; Animals; Apoptosis; Binding; Biology; Biology of Aging; Biosensor; Cancer Patient; Cells; Chimera organism; Chromatin; Clinic; Code; Complement; DNA Repair; Defect; Deltastab; Deposition; Diagnosis; Disabled Persons; Disease; Drosophila genus; Elements; Epigenetic Process; Fishes; Gene Family; Genes; Genetic; Genetic Models; Genetic Transcription; Genome; Goals; Health; Heritability; Human; Human Pathology; Hyperactivity; Individual; Instruction; Link; Malignant Neoplasms; Mediating; Modality; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Oncogenic; Pathology; Phenotype; Positioning Attribute; Process; Property; Protein Isoforms; Proteins; Regulation; Reporting; Repression; Resources; Retroelements; Retrotransposon; Route; Specific qualifier value; Stress; System; TP53 gene; Time; Trans-Activators; Transcriptional Activation; Tumor Suppression; age related; biological adaptation to stress; cancer prevention; cell growth; cell injury; fly; genome-wide; human disease; improved; in vivo; innovation; insight; loss of function; mutant; prevent; reconstitution; response; senescence; tool; transcription factor; tumor; virtual

Summary The p53 gene family occupies central positions in stress response networks throughout the animal kingdom and, as transcription factors, these proteins specify robust adaptive responses. Furthermore, the human counterpart is broadly implicated in age-related diseases including most cancers. Yet despite extensive characterization, disease deterrence by p53 is not well understood and conventional explanations for how p53 prevents oncogenic transformation have been fundamentally challenged. Since p53 genes are broadly conserved, ancestral properties of these genes offer promising routes towards understanding functions that become deranged in human diseases. Toward this goal, we built tools to explore the p53 regulatory network in genetic models, enabling unique opportunities to interrogate conserved properties that support human pathologies. These resources include in vivo biosensors that visualize real-time p53 action and complementation platforms that exchange human alleles for the fly counterpart. Leveraging these tools in flies and in fish, we discovered that p53 is acutely sensitive to - and normally restrains - retrotransposons, which are mobile elements broadly implicated in human disease. Likewise, we further showed that human p53 genes could similarly restrain transposons, but mutated p53 alleles from cancer patients could not. These combined discoveries suggest that p53 acts through highly conserved mechanisms to restrict transposons. Furthermore, since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates disease, in part, by suppressing the activity of transposons. Consistent with this, we exposed hyperactive retrotransposons in p53-driven cancers and found co-repression activity that is obligate for p53 suppression. Initiatives advanced in this proposal build on these discoveries to determine precisely how p53 restrains mobile elements. Our approach integrates genetic models with molecular systems to deconstruct this process. Within this framework, we may deliver new opportunities for improved diagnosis and treatment of conditions fueled by dysfunctional p53.

总结 p53基因家族在整个动物的应激反应网络中占据中心位置 作为转录因子，这些蛋白质指定了强大的适应性反应。此外，委员会还认为， 人类对应物与包括大多数癌症在内的与年龄有关的疾病广泛相关。然而尽管 广泛的表征，p53的疾病威慑尚未得到很好的理解和常规 对p53如何阻止致癌转化的解释已经受到根本性的挑战。 由于p53基因是广泛保守的，这些基因的祖先特性提供了有前途的路线 对理解人类疾病中的紊乱功能有很大的帮助。为了实现这一目标，我们建立了 在遗传模型中探索p53调控网络的工具，使独特的机会， 询问支持人类病理学的保守特性。这些资源包括体内 实时可视化p53作用和互补平台的生物传感器， 果蝇的等位基因利用苍蝇和鱼类的这些工具，我们发现p53是 对反转录转座子非常敏感，通常会抑制反转录转座子，反转录转座子是广泛的移动的元件 与人类疾病有关同样，我们进一步表明，人类p53基因可以类似地抑制 转座子，但突变的p53等位基因从癌症患者不能。这些综合发现 表明p53通过高度保守的机制来限制转座子。此外，由于 人类p53突变体不能进行这种活性，我们的发现提高了p53减轻这种活性的可能性。 疾病，部分是通过抑制转座子的活性。与此相一致，我们暴露了 在p53驱动的癌症中过度活跃的反转录转座子，并发现了专性的共抑制活性， p53抑制。该提案中提出的倡议建立在这些发现的基础上， p53如何抑制移动的元素。我们的方法将遗传模型与分子系统相结合， 解构这个过程。在这个框架内，我们可以提供新的机会， 诊断和治疗由功能失调的p53引起的病症。