Published July 4, 2025 | Version v1
Report Open

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

Authors/Creators

  • 1. ROR icon Ludwig Cancer Research
  • 2. ROR icon The Netherlands Cancer Institute
  • 3. ROR icon Radboud University Nijmegen
  • 4. ROR icon Eindhoven University of Technology
  • 5. ROR icon Delft University of Technology
  • 6. Netherlands Cancer Institute
  • 7. ROR icon Oncode Institute

Description

Abstract - Zinc finger proteins (ZNFs) are the largest family of transcription factors, yet how theyactivate gene expression remains unclear. Here, we identify and study Zincore, an uncharacterizedprotein complex consisting of QRICH1 and SEPHS1, as a novel ZNF-specific coregulator. BothQRICH1 and SEPHS1 are critical for embryonic development in mice and their haploinsufficiencyis linked to similar neurodevelopmental defects in humans. Among Zincore clients, we identifyZFP91 as the transcription factor that binds to the evolutionary conserved motif CTTTAAR. The cryo-EM structure of Zincore in complex with ZFP91 bound to this motif, reveals Zincoreto recognise the DNA-bound zinc finger domains, explaining the recognition of a wide variety ofZNFs. Surprisingly, this interaction stabilizes the binding of ZFP91 to the DNA, thereby lockingit on its consensus motif, providing a unique activity for a transcriptional coregulator. Thus, ourstudy reveals Zincore as ZNF-specific coregulator essential for embryonic development, involvingan unprecedented mechanism to lock ZNFs onto DNA and regulate transcription.


This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on July 4th 2025, DOI: DOI: 10.1126/science.adv2861

Files

250611_acceptedfinal.pdf

Files (52.0 MB)

Name Size Download all
md5:3e82239e56c36aec7006b6f395080ce6
52.0 MB Preview Download