{"id":523,"title":"MYC primes a paralog synthetic lethality involving the mitochondrial translocase subunits TIMM17A and TIMM17B and N-Acetylaspartate","title_zh":"MYC 通过抑制 TIMM17B 制造旁系同源合成致死依赖，N-乙酰天冬氨酸可挽救该依赖","url":"https://doi.org/10.1126/sciadv.aej2662","doi":"10.1126/sciadv.aej2662","pmid":null,"journal":"Science Advances","kind":"paper","lang":"en","published_at":"2026-11-06T00:00:00+00:00","fetched_at":"2026-11-08T03:45:21+00:00","authors":["Sydney M. Moyer","Nina Ilic","Sydney Gang","Lucas Dailey","Sehyun Oh","Jasmine Stavridi","Gaia Taig","Kathia E. Rodarte","Joseph D. DeAngelo","Andrea Jiang","Brian H. Shim","Jonathan P. Rennhack","John R. Jacob","Melis A. Akinci","Jonathan So","Helen Wang","Federica Piccioni","Jessica A. Talamas","Hans R. Widlund","David E. Root","Clary B. Clish","Nika N. Danial","William C. Hahn"],"primary_topic":"repro-aging","topics":[{"slug":"repro-aging","score":4.0,"hits":["mitochondrial"]},{"slug":"ethics-policy","score":1.0,"hits":["crispr"]}],"topic_score":4.0,"preference_score":0.0,"preference_labels":[],"llm_score":42.0,"final_score":50.0,"score_dims":{"novelty":72,"rigor":78,"impact":25,"relevance":10,"translation":15},"recommend_reason":"这是一项设计扎实的肿瘤功能基因组学研究（全基因组 CRISPR 筛选加代谢物挽救验证），但不涉及生殖、胚胎或 ART 任何环节，与本草道读者关注的方向基本无关，仅对关注线粒体蛋白输入或合成致死策略的读者有间接参考价值。","keywords":["MYC","合成致死","TIMM17A/TIMM17B","线粒体蛋白转运","N-乙酰天冬氨酸","CRISPR 筛选"],"selected":0,"story_id":11,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"crossref-cns","source_name":"Crossref · CNS 与大子刊新上线（领域过滤）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"sci-adv","journal_tier":"cns-sub","journal_if":11.7,"is_mock":false,"summary_zh":"为寻找 MYC 扩增肿瘤的必需基因，作者构建了由致癌 MYC 驱动转化的同源细胞体系，并用全基因组 CRISPR-Cas9 文库筛选，发现线粒体膜转位酶 TIMM17A 对 MYC 转化细胞的存活独一无二地必需。机制在于 MYC 抑制 TIMM17A 的旁系同源基因 TIMM17B；而 TIMM17A/B 是 TIM23 线粒体蛋白输入复合体的核心组分，故形成对 TIMM17A 的强依赖。补充 N-乙酰天冬氨酸可挽救 MYC 扩增细胞系的 TIMM17A 依赖，提示该代谢物对 MYC 扩增肿瘤的适应度至关重要。研究鉴定了部分 MYC 驱动肿瘤所需的旁系同源依赖，属肿瘤代谢与功能基因组学范畴。","summary":"To identify the genes and pathways required for the survival of MYC -amplified cancers, we engineered an isogenic cell system in which transformation is driven by oncogenic MYC. Using a genome-scale CRISPR-Cas9 library, we identified the mitochondrial membrane translocase TIMM17A as uniquely essential for the survival of MYC-transformed cells. This dependency arises from MYC-driven suppression of TIMM17B, the paralog of TIMM17A. TIMM17A/B is an essential component of the TIM23 mitochondrial protein import complex, and the MYC-induced suppression of TIMM17B creates a strong dependency on TIMM17A. N-acetylaspartate supplementation rescued TIMM17A dependency in MYC -amplified cell lines, highlighting the unique and crucial role of this metabolite in the cell fitness of MYC -amplified cancers. These observations identify a paralog dependency required for the survival of a subset of MYC-driven cancers.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}