ASB7 is a negative regulator of H3K9me3 homeostasis

• 成果类型: Article
• 署名作者: Zhou, Liwen; Chen, Zhenxuan; Zou, Yezi; Zhang, Xia; Wang, Zifeng; Zhu, Hongwen; Lin, Jiahui; Huang, Ziyao; Zheng, Lisi; Chen, Jiali; Xie, Miner; Zhang, Meifang; Zhang, Ruhua; Zhu, Minglu; Wang, Ziwen; Zhou, Hu; Gao, Song; Yin, Yuxin; Wu, Yuanzhong; Kang, Tiebang
• 署名单位: State Key Lab Oncology South China; Sun Yat Sen University; Sun Yat Sen University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; South China University of Technology; Peking University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12145
• DOI: 10.1126/science.adq7408
• 发表日期: 2025-07-17
• 页码: 309-316
• 关键词: heterochromatin protein-1 hp1; histone h3; phase-separation; binding-site; lysine 9; chromatin; methyltransferase; methylation; RECOGNITION; complex

摘要

The maintenance of histone H3 lysine 9 trimethylation (H3K9me3) involves the recognition of preexisting modifications by heterochromatin protein 1 (HP1), which recruits the methyltransferase suppressor of variegation 3-9 homolog 1 (SUV39H1) to methylate the adjacent newly incorporated histones, establishing a positive feedback loop. However, how this positive feedback is restricted to maintain H3K9me3 homeostasis remains largely unknown. We performed an unbiased genome-scale CRISPR-Cas9 screen and identified CUL5ASB7 E3 ubiquitin ligase as a negative regulator of H3K9me3. ASB7 is recruited to heterochromatin by HP1 and promotes SUV39H1 degradation. During mitosis, cyclin-dependent kinase 1 (CDK1) phosphorylates ASB7, preventing its interaction with SUV39H1, leading to SUV39H1 stabilization and H3K9me3 restoration. Our findings reveal a dynamic circuit involving HP1, SUV39H1, and ASB7 that governs H3K9me3 homeostasis, ensuring faithful epigenetic inheritance and preventing excessive heterochromatin formation.