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MYC drives left-handed Z-DNA formation to shape gene expression
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MYC drives left-handed Z-DNA formation to shape gene expression
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Journal Article
MYC drives left-handed Z-DNA formation to shape gene expression
2025
Overview
DNA topology is critical for regulating transcription and maintaining cellular homeostasis. Z-DNA is a left-handed DNA helix in regions with high transcriptional activity. Its physiological function remains poorly understood. Here, we demonstrate that oncoprotein MYC induces the formation of Z-DNA by recruiting the chromatin remodeler FACT, independent of RNA Polymerase II activity. FACT facilitates Z-DNA formation by remodeling H2A/H2B dimers within intact nucleosomes. Additionally, the phosphorylation of FACT regulates its liquid-liquid phase separation, promoting its efficient recruitment to chromatin by MYC. Through a genome-wide analysis and characterization of engineered Z-DNA promoters, we found that Z-DNA directly facilitates the loading of RNA Polymerase II, thereby promoting transcriptional activity. This study elucidates the molecular mechanisms of Z-DNA dynamics and emphasizes its functional importance in transcriptional regulation, providing insights into the role of left-handed DNA structures in chromatin biology and MYC-driven cancer.
Z-DNA forms at highly active genes, but its function is unclear. Here, the authors show that MYC recruits FACT to promote Z-DNA formation within nucleosomes, enabling RNA Polymerase II loading and enhancing transcription, revealing a mechanistic role for Z-DNA in MYC-driven regulation.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 45/15
/ 45/43
/ Chromatin Assembly and Disassembly
/ DNA
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Proteins
/ Proto-Oncogene Proteins c-myc - genetics
/ Proto-Oncogene Proteins c-myc - metabolism
/ RNA
/ RNA Polymerase II - metabolism
/ Science
/ Topology
/ Z-form
