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

基本信息

批准号：
10709000
负责人：
Jan Karlseder
金额：
$ 61.33万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
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/10709000
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 Chromosomal Breaks Clustered Regularly Interspaced Short Palindromic Repeats Complex Cytoplasm Cytoprotection 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 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 Viral Z-DNA Binding Protein age related anti-cancer biomarker identification 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 structural determinants telomere transcriptome tumor viral DNA viral detection

项目摘要

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.

项目概要细胞核到线粒体核酸传感途径可防止年龄相关的绕过增殖边界作为年龄函数的永生的发展取决于细胞逃离至少两种物质的能力明显的增殖障碍、复制衰老和危机。两者都是重要的肿瘤抑制剂，但管理它们的途径是不同的。复制性衰老是由短功能端粒引发的，依赖于 p53/pRB 肿瘤抑制途径，其特征是永久细胞周期停滞和持续新陈代谢。当 p53/pRB 通路功能失调时，衰老进入就会受到损害，细胞继续增殖，直到它们的端粒变得功能失调并且出现染色体融合。这会触发复制危机，一种 p53/pRB 独立状态，绝大多数细胞迅速死亡。然而，稀有细胞甚至可以克服这一障碍并成为肿瘤细胞，这表明复制危机是一种对抗与年龄相关的肿瘤细胞起始的最终障碍。最近，人们发现细胞死亡危机是由巨自噬通过一条途径控制的，在该途径中，细胞质 DNA 物种来自融合和断裂的染色体激活通常检测病毒的 cGAS-STING 细胞质 DNA 传感反应脱氧核糖核酸。抑制自噬使细胞绕过危机并继续增殖，同时积累基因组不稳定。这一发现代表了第一个危机旁路系统，它允许设计一个 CRISPR 抑制筛选旨在识别保护细胞免受年龄相关癌症所需的因素引发。另一种核酸传感器 ZBP1 对危机计划至关重要，这一点得到了 ZBP1 抑制使细胞能够在危机后增殖。在此，建议实现三个协同目标：破译 ZBP1 依赖性抑制癌症发生的机制。 AIM1 将确定功能失调的端粒、端粒 (TERRA) 转录本和 ZBP1 之间的相互作用并定义危机期间 ZBP1 介导的线粒体先天免疫信号传导机制。 AIM2 旨在研究ZBP1危机特异性亚型的线粒体定位机制及其相关互动的伙伴。最后，让细胞在危机后增殖的能力揭示了第三种因素的存在以前未知的阻止癌症发生的增殖屏障（称为 M3），这将被广泛应用 AIM 3 中的特征。成功完成这些目标将为端粒之间的串扰提供新的线索，线粒体和炎症（衰老的三个既定标志）、端粒到线粒体的作用先天免疫信号通路预防与年龄相关的癌症并建立生物标志物和新的方法来了解新的 M3 增殖屏障作为肿瘤抑制剂的相关性。