Zincore, an atypical coregulator, binds zinc finger transcription factors to control gene expression

• 成果类型: Article
• 署名作者: Bianchi, Danielle; Borza, Razvan; De Zan, Erica; Huelsz-Prince, Guizela; Gregoricchio, Sebastian; Dekker, Marleen; Fish, Alex; Mazouzi, Abdelghani; Kroese, Lona J.; Linder, Simon; Hernandez-Quiles, Miguel; Vermeulen, Michiel; Celie, Patrick H. N.; Krimpenfort, Paul; Song, Ji-Ying; Zwart, Wilbert; Wessels, Lodewyk; Nijman, Sebastian M. B.; Perrakis, Anastassis; Brummelkamp, Thijn R.
• 署名单位: Netherlands Cancer Institute; University of Oxford; Ludwig Institute for Cancer Research; University of Oxford; Netherlands Cancer Institute; Netherlands Cancer Institute; Netherlands Cancer Institute; Netherlands Cancer Institute; Radboud University Nijmegen; Netherlands Cancer Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10320
• DOI: 10.1126/science.adv2861
• 发表日期: 2025-07-03
• 关键词: map; identification; purification; interactome; mutations; apoptosis; requires; reveal

摘要

Zinc finger proteins (ZNFs) are the largest family of transcription factors, yet how they activate gene expression remains unclear. In this study, we identified Zincore, a protein complex consisting of QRICH1 and SEPHS1, as a ZNF-specific coregulator essential for embryonic development in mice and associated with developmental syndromes in humans. We also identified ZFP91 as a representative Zincore client, binding the conserved promoter motif CTTTAAR. Cryo-electron microscopy of a Zincore-ZFP91-DNA complex revealed a SEPHS1 arginine clamp to recognize the DNA-bound zinc finger domains. This mode of binding explains recognition of different ZNFs and stabilizes ZFP91 onto its cognate DNA motif. Thus, our study identified Zincore as a ZNF-specific coregulator essential for development, involving a distinctive mechanism that locks ZNFs onto DNA and regulates transcription.