{"id":397,"title":"SMURFs regulate mesendoderm differentiation through SMAD2-dependent ubiquitination of CDK9","title_zh":"SMURF1/2 通过 SMAD2 依赖的 CDK9 泛素化调控中内胚层分化","url":"https://pubmed.ncbi.nlm.nih.gov/42905518","doi":"10.1016/j.celrep.2026.118172","pmid":"42905518","journal":"Cell Rep","kind":"paper","lang":"en","published_at":"2026-10-20T00:00:00+00:00","fetched_at":"2026-11-08T03:44:12+00:00","authors":["Shin JH","Xu X","Xiao T","Tang Y","Molla MR","Chen T","Chen Q","Du Y","Liu C","Zhang YE"],"primary_topic":"early-embryo","topics":[{"slug":"early-embryo","score":2.0,"hits":["gastrulation","lineage specification"]},{"slug":"ethics-policy","score":2.0,"hits":["regulation","regulatory"]}],"topic_score":2.0,"preference_score":0.0,"preference_labels":[],"llm_score":66.0,"final_score":74.0,"score_dims":{"novelty":80,"rigor":78,"impact":62,"relevance":55,"translation":38},"recommend_reason":"机制清晰、补充了 Nodal/SMAD2 转录程序在原肠胚形成期如何被终止这一空白，对早期胚胎谱系决定研究有价值；但属基础发育生物学，与 ART 实验室与临床决策的直接关联较弱。","keywords":["SMURF1/2","CDK9","SMAD2","中内胚层分化","Pol II 启动子近端暂停","泛素化降解"],"selected":1,"story_id":359,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-top-journals","source_name":"PubMed · CNS/大子刊/四大医学刊（生殖相关）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"cell-rep","journal_tier":"cns-sub","journal_if":7.5,"is_mock":false,"summary_zh":"该研究以小鼠/胚胎模型（原文摘要未明确物种与具体实验体系）探讨 Nodal-SMAD2 转录程序在早期胚胎发育中如何被适时衰减。作者发现 E3 泛素连接酶 SMURF1 与 SMURF2 是 SMAD2 驱动转录的关键负调控因子：二者泛素化 CDK9 并促其经蛋白酶体降解，从而限制 CDK9 依赖的 RNA 聚合酶 II 启动子近端暂停释放及 SMAD2 靶基因的有效转录延伸。SMURF 功能缺失可使 CDK9 稳定、其在 SMAD2 靶基因上的占位增加、Pol II 暂停释放增强，中内胚层基因表达持续升高。研究揭示了一种泛素依赖的形态发生素信号“刹车”机制，保障发育进程的时序性。","summary":"Precise control of transcriptional timing is essential during embryonic development, where dynamic gene expression programs govern lineage specification. Promoter-proximal pausing of RNA polymerase II (Pol II) and its regulated release into productive elongation constitute a critical checkpoint in transcriptional regulation. Nodal, a transforming growth factor β (TGF-β) family morphogen, promotes mesendoderm differentiation through SMAD2-dependent transcription, in part by promoting cyclin-dependent kinase 9 (CDK9)-mediated release of paused Pol II. While mechanisms of transcriptional activation downstream of Nodal are well characterized, how this transcriptional program is attenuated during gastrulation remains unclear. Here, we show that E3 ubiquitin ligases SMAD Ubiquitination Regulatory Factor (SMURF) 1 and SMURF2 are critical regulators of SMAD2-driven transcription. SMURF1/2 ubiquitinate CDK9 and promote its proteasome-mediated degradation, thereby restraining CDK9-dependent promoter-proximal pause release and productive transcription of SMAD2-dependent genes. Loss of SMURF function stabilizes CDK9, increases its occupancy at SMAD2 target genes, and enhances Pol II pause release, thereby sustaining mesendodermal gene expression. These findings reveal a ubiquitin-dependent mechanism that restricts morphogen-induced gene expression and ensures timely developmental progression.","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}}