A nucleus-to-mitochondria nucleic acid-sensing pathway prevents bypass of age-associated proliferative boundaries

细胞核到线粒体核酸传感途径可防止绕过与年龄相关的增殖边界

• 批准号: 10587704
• 负责人: Jan Karlseder
• 金额: $ 59.87万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587704
• 关键词: Age; Aging; Alternative Splicing; Anchorage-Independent Growth; Autophagocytosis; Binding; Biological Markers; Biology; Bypass; CRISPR screen; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cell Death; Cell Nucleus; Cells; Characteristics; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA; DNA Damage; Data; Dependence; Development; Exhibits; Functional disorder; Gene Expression Profiling; Genomic Instability; Human; Immune; Immune signaling; Individual; Inflammation; Inflammatory; Innate Immune System; Interferons; Knock-out; Light; Malignant Neoplasms; Mediating; Metabolism; Mitochondria; Molecular; Neoplastic Cell Transformation; Nuclear; Nucleic Acid Binding; Nucleic Acids; Organism; Outer Mitochondrial Membrane; Pathway interactions; Phenotype; Play; Premalignant Cell; Prevention; Proliferating; Protein Isoforms; Proteins; RNA; RNA Sequences; RNA Splicing; Retinoblastoma Protein; Role; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stimulator of Interferon Genes; System; TP53 gene; Telomere Shortening; Testing; Transcript; Tumor Escape; Tumor Suppressor Proteins; Variant; Z-DNA Binding Protein; age related; anti-cancer; base; cancer cell; cancer initiation; chromosome fusion; cytokine; design; genome wide screen; in vivo; mitochondrial genome; mortality; neoplastic; neoplastic cell; novel; novel strategies; prevent; programs; response; senescence; sensor; telomere; transcriptome; tumor; viral DNA

Project Summary A nucleus-to-mitochondria nucleic acid-sensing pathway prevents bypass of age-associated proliferative boundaries Development of immortality as function of age is dependent on the ability of cells to escape from at least two distinct proliferative barriers, replicative senescence and crisis. Both serve as critical tumor-suppressors, but the pathways governing them are distinct. Replicative senescence is triggered by short functional telomeres, dependent on the p53/pRB tumor suppressor pathways and characterized by permanent cell cycle arrest and continued metabolism. When p53/pRB pathways are dysfunctional, senescence entry is compromised, and cells continue to proliferate until their telomeres become dysfunctional and chromosome fusions arise. This triggers replicative crisis, a p53/pRB-independent state, where the vast majority of cells rapidly succumb to cell death. However, rare cells can even overcome this barrier and become neoplastic, pointing to replicative crisis as one of the final barriers against age-associated tumor cell initiation. Recently, it was discovered that cell death in crisis is governed by macroautophagy through a pathway in which cytoplasmic DNA species from fused and broken chromosomes activate the cGAS-STING cytoplasmic DNA-sensing response that normally detects viral DNA. Suppression of autophagy allowed cells to bypass crisis and continue to proliferate, while accumulating genome instability. This discovery represented the first crisis-bypass system, which allowed the design of a CRISPR suppression screen aimed at identifying factors required to protect cells against age-associated cancer initiation. Another nucleic acid sensor, ZBP1 emerged as critical for the crisis program, which was confirmed by ZBP1 suppression allowing cells to proliferate beyond crisis. Here, in three synergistic aims it is proposed to decipher the mechanism underlying the ZBP1-dependent inhibition of cancer initiation. AIM1 will determine the interactions between dysfunctional telomeres, telomeric (TERRA) transcripts and ZBP1 and define the mechanisms of ZBP1-mediated innate immune signaling on mitochondria during crisis. AIM2 is designed to investigate the mechanism of the mitochondrial localization of the crisis-specific isoform of ZBP1 and its relevant interacting partners. Finally, the ability to allow cells to proliferate beyond crisis revealed the existence of a third previously unknown proliferative barrier against cancer initiation (called M3), which will be extensively characterized in AIM 3. Successful completion of these aims will shed new light on crosstalk between telomeres, mitochondria and inflammation (three established hallmarks of aging), the role of a telomere-to-mitochondria innate immune signaling pathway in the prevention of age-associated cancer and establish biomarkers and new approaches to understand the relevance of the new M3 proliferative barrier as tumor-suppressor.

项目摘要 核到线粒体的核酸传感途径防止年龄相关的旁路 增生边界 随着年龄的增长，永生的发展取决于细胞逃离至少两种细胞的能力。 明显的增殖屏障、复制性衰老和危机。两者都是重要的肿瘤抑制剂，但 控制它们的途径是不同的。复制性衰老是由短的功能性端粒引发的， 依赖于p53/pRB肿瘤抑制途径，特征为永久性细胞周期停滞， 持续的新陈代谢。当p53/pRB通路功能障碍时，衰老进入受到损害，细胞 继续增殖，直到它们的端粒变得功能失调，染色体融合出现。这触发 复制危机，一种p53/pRB非依赖性状态，其中绝大多数细胞迅速屈服于细胞死亡。 然而，罕见的细胞甚至可以克服这一障碍，成为肿瘤，指出复制危机之一， 年龄相关的肿瘤细胞启动的最终障碍。最近，人们发现， 危机是由宏观自噬通过一个途径，其中细胞质DNA物种从融合和 断裂的染色体激活cGAS-STING细胞质DNA感应反应， DNA.抑制自噬使细胞绕过危机，继续增殖，同时积累 基因组不稳定性这一发现代表了第一个危机旁路系统，它允许设计一个 CRISPR抑制筛选旨在确定保护细胞免受年龄相关癌症所需的因素 入会仪式另一种核酸传感器ZBP1对危机计划至关重要，这一点得到了证实。 ZBP1抑制允许细胞增殖超过危机。这里，在三个协同目标中，建议 破译ZBP1依赖性抑制癌症发生的机制。AIM1将决定 功能失调的端粒，端粒（TERRA）转录本和ZBP 1之间的相互作用，并定义了 危机期间ZBP1介导的线粒体先天免疫信号传导的机制。AIM2设计用于 探讨ZBP 1危机特异性亚型的线粒体定位机制及其相关性 互动伙伴最后，让细胞在危机后增殖的能力揭示了第三种细胞的存在。 以前未知的针对癌症起始的增殖屏障（称为M3），这将被广泛研究。 在AIM 3中。这些目标的成功完成将为端粒之间的串扰提供新的线索， 线粒体和炎症（三个既定的衰老标志），端粒对线粒体的作用 先天免疫信号通路在预防年龄相关性癌症和建立生物标志物和新的 了解新的M3增殖屏障作为肿瘤抑制剂的相关性的方法。