MYC drives left-handed Z-DNA formation to shape gene expression
Year: 2025
Type: article
Abstract: 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.
Source: Nature Communications
Authors: Xinyi Wan, Haonan Fan, Zhuoning Li, Yixuan Du, Yu Liu, Weiwu Zeng, Zhongxing Sun, Juejia Shao, Junqi Jia, Yanjun Zhang, Dong Fang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W4416837046