{"title":"Integrator 20th anniversary: a molecular machine indispensable in development and disease.","authors":"Mina M Tayari, Ramin Shiekhattar","doi":"10.1016/j.molmed.2025.09.003","DOIUrl":null,"url":null,"abstract":"<p><p>The Integrator complex, composed of at least 19 subunits, associates with RNA polymerase II (RNAPII) and exerts critical roles in transcriptional regulation. By interacting with the C-terminal domain (CTD) of RNAPII, it cleaves nascent RNA transcripts, leading to termination of non-productive transcription in protein-coding genes and processing of diverse noncoding RNAs. Beyond RNA cleavage, Integrator regulates transcription initiation, pause-release, and elongation, while also processing enhancer RNAs. It contributes to genome stability by modulating RNAPII activity during DNA damage and replication stress. Dysfunction of Integrator subunits has been linked to neurodevelopmental disorders and cancer, underscoring its broad physiological significance. This review highlights recent advances in structure and function that illuminate Integrator's essential roles in development, neurobiology, and disease.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":13.8000,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Trends in molecular medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.molmed.2025.09.003","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The Integrator complex, composed of at least 19 subunits, associates with RNA polymerase II (RNAPII) and exerts critical roles in transcriptional regulation. By interacting with the C-terminal domain (CTD) of RNAPII, it cleaves nascent RNA transcripts, leading to termination of non-productive transcription in protein-coding genes and processing of diverse noncoding RNAs. Beyond RNA cleavage, Integrator regulates transcription initiation, pause-release, and elongation, while also processing enhancer RNAs. It contributes to genome stability by modulating RNAPII activity during DNA damage and replication stress. Dysfunction of Integrator subunits has been linked to neurodevelopmental disorders and cancer, underscoring its broad physiological significance. This review highlights recent advances in structure and function that illuminate Integrator's essential roles in development, neurobiology, and disease.
期刊介绍：
Trends in Molecular Medicine (TMM) aims to offer concise and contextualized perspectives on the latest research advancing biomedical science toward better diagnosis, treatment, and prevention of human diseases. It focuses on research at the intersection of basic biology and clinical research, covering new concepts in human biology and pathology with clear implications for diagnostics and therapy. TMM reviews bridge the gap between bench and bedside, discussing research from preclinical studies to patient-enrolled trials. The major themes include disease mechanisms, tools and technologies, diagnostics, and therapeutics, with a preference for articles relevant to multiple themes. TMM serves as a platform for discussion, pushing traditional boundaries and fostering collaboration between scientists and clinicians. The journal seeks to publish provocative and authoritative articles that are also accessible to a broad audience, inspiring new directions in molecular medicine to enhance human health.
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