Human HDAC6 senses valine abundancy to regulate DNA damage

• 成果类型: Article
• 署名作者: Jin, Jiali; Meng, Tong; Yu, Yuanyuan; Wu, Shuheng; Jiao, Chen-Chen; Song, Sihui; Li, Ya-Xu; Zhang, Yu; Zhao, Yuan-Yuan; Li, Xinran; Wang, Zixin; Liu, Yu-Fan; Huang, Runzhi; Qin, Jieling; Chen, Yihua; Cao, Hao; Tan, Xiao; Ge, Xin; Jiang, Cong; Xue, Jianhuang; Yuan, Jian; Wu, Dianqing; Wu, Wei; Jiang, Ci-Zhong; Wang, Ping
• 署名单位: Tongji University; Shanghai Jiao Tong University; Tongji University; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; Tongji University; East China Normal University; Kunming Medical University; Kunming Medical University; Kunming Medical University; Shenyang Pharmaceutical University; Tongji University; Yale University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1474
• DOI: 10.1038/s41586-024-08248-5
• 发表日期: 2025-01-02
• 关键词: amino-acid-metabolism; genome-wide; demethylation; protein; methylation; 5-hydroxymethylcytosine; signals; binding; sites

摘要

As an essential branched amino acid, valine is pivotal for protein synthesis, neurological behaviour, haematopoiesis and leukaemia progression1, 2-3. However, the mechanism by which cellular valine abundancy is sensed for subsequent cellular functions remains undefined. Here we identify that human histone deacetylase 6 (HDAC6) serves as a valine sensor by directly binding valine through a primate-specific SE14 repeat domain. The nucleus and cytoplasm shuttling of human, but not mouse, HDAC6 is tightly controlled by the intracellular levels of valine. Valine deprivation leads to HDAC6 retention in the nucleus and induces DNA damage. Mechanistically, nuclear-localized HDAC6 binds and deacetylates ten-eleven translocation 2 (TET2) to initiate active DNA demethylation, which promotes DNA damage through thymine DNA glycosylase-driven excision. Dietary valine restriction inhibits tumour growth in xenograft and patient-derived xenograft models, and enhances the therapeutic efficacy of PARP inhibitors. Collectively, our study identifies human HDAC6 as a valine sensor that mediates active DNA demethylation and DNA damage in response to valine deprivation, and highlights the potential of dietary valine restriction for cancer treatment.