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

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:
10709000
负责人:
Jan Karlseder
金额:
$61.33万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-30 至 2027-06-30

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中文摘要
翻译
项目摘要 细胞核到线粒体的核酸传感通路阻止AGE相关的旁路 增殖性边界 作为年龄函数的永生化的发展取决于细胞逃离至少两个细胞的能力 明显的增殖障碍、复制衰老和危机。两者都是关键的肿瘤抑制因子,但 管理它们的路径是不同的。复制衰老是由功能较短的端粒触发的, 依赖于P53/PRB肿瘤抑制通路,其特征是永久性的细胞周期停滞和 持续新陈代谢。当P53/PRB通路功能障碍时,衰老进入受到影响,细胞 继续增殖,直到它们的端粒功能失调,出现染色体融合。这会触发 复制危机,一种不依赖于p53/pRb的状态,绝大多数细胞迅速死于细胞死亡。 然而,罕见的细胞甚至可以克服这一障碍并成为肿瘤,这表明复制危机是一体的。 阻止与年龄相关的肿瘤细胞启动的最后障碍。最近,人们发现,细胞死亡在 危机是由巨大的自噬控制的,通过一条途径,细胞质DNA物种来自融合和 断裂的染色体激活了正常情况下检测病毒的cGAS刺状细胞质DNA传感反应 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。这一发现代表了第一个危机旁路系统,它允许设计一种 CRISPR抑制筛查旨在识别保护细胞免受年龄相关癌症影响所需的因素 入会仪式。另一种核酸传感器ZBP1成为危机计划的关键,这一点得到了 ZBP1的抑制使细胞能够在危机后增殖。在这里,在三个协同目标中,它被提议 破译ZBP1依赖抑制癌症启动的机制。AIM1将决定 功能失调的端粒、端粒(Terra)转录本与ZBP1之间的相互作用 危机时ZBP1介导的线粒体天然免疫信号机制。AIM2旨在 ZBP1危象特异性亚型的线粒体定位机制及其相关研究 互动伙伴。最后,让细胞在危机后继续增殖的能力揭示了第三种细胞的存在。 以前未知的抗肿瘤启动的增殖屏障(称为M3),它将被广泛地 这些目标的成功完成将为研究端粒之间的串扰提供新的线索, 线粒体和炎症(三个公认的衰老标志),端粒到线粒体的作用 天然免疫信号通路在预防老年癌症中的作用及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因子的相关性的方法。
英文摘要
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.
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A nucleus-to-mitochondria nucleic acid-sensing pathway prevents bypass of age-associated proliferative boundaries
Spontaneous replication fork collapse regulates telomere length homeostasis in wild type yeast
Spontaneous replication fork collapse regulates telomere length homeostasis in wild type yeast
Understanding the role of autophagy-regulated cell death in the escape from replicative crisis
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