2. Academic Validation
  3. Human HDAC6 senses valine abundancy to regulate DNA damage

Human HDAC6 senses valine abundancy to regulate DNA damage

  • Nature. 2024 Nov 20. doi: 10.1038/s41586-024-08248-5.
Jiali Jin # 1,  Tong Meng # 1 2,  Yuanyuan Yu # 3,  Shuheng Wu # 4,  Chen-Chen Jiao 1,  Sihui Song 1,  Ya-Xu Li 1,  Yu Zhang 1,  Yuan-Yuan Zhao 1,  Xinran Li 1,  Zixin Wang 5,  Yu-Fan Liu 1,  Runzhi Huang 1,  Jieling Qin 1,  Yihua Chen 6 7,  Hao Cao 8,  Xiao Tan 1,  Xin Ge 1,  Cong Jiang 1,  Jianhuang Xue 5,  Jian Yuan 9,  Dianqing Wu 10,  Wei Wu 4,  Ci-Zhong Jiang 3,  Ping Wang 11
Affiliations

Affiliations

  • 1 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 2 Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
  • 3 Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 4 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 5 Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital affiliated to Tongji University, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 6 Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China.
  • 7 School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products and Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming, China.
  • 8 School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
  • 9 Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China.
  • 10 Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA.
  • 11 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China. wangp@tongji.edu.cn.
  • # Contributed equally.
PMID: 39567688 DOI: 10.1038/s41586-024-08248-5
Abstract

As an essential branched amino acid, valine is pivotal for protein synthesis, neurological behaviour, haematopoiesis and leukaemia progression1-3. 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.

Figures
Products