同济大学王平等合作发现，人源HDAC6通过感知缬氨酸丰度来调节DNA损伤。相关论文于2024年11月20日发表在《自然》杂志上。

研究人员表示，缬氨酸作为一种必需的支链氨基酸，在蛋白质合成、神经行为、造血和白血病进展中起着关键作用。然而，细胞缬氨酸丰度对后续细胞功能的感知机制仍未明确。

该研究组确定了人源组蛋白去乙酰化酶6 （HDAC6），通过灵长类动物特异性SE14重复结构域直接结合缬氨酸，起到缬氨酸传感器的作用。人类细胞核和细胞质的穿梭受胞内缬氨酸水平的严格控制。缬氨酸剥夺导致HDAC6保留在核核中并诱导DNA损伤。

机制上，核定位的HDAC6结合和去乙酰化TET2启动活跃的DNA去甲基化，通过胸腺嘧啶DNA糖基化酶驱动的切除促进DNA损伤。饮食限制缬氨酸抑制异种移植和患者来源的异种移植模型的肿瘤生长，并增强PARP抑制剂的治疗效果。

总的来说，他们的研究确定了人类HDAC6作为一种缬氨酸传感器，在缬氨酸剥夺的反应中介导活跃的DNA去甲基化和DNA损伤，并强调了限制饮食缬氨酸治疗癌症的潜力。

附：英文原文

Title: Human HDAC6 senses valine abundancy to regulate DNA damage

Author: 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

Issue&Volume: 2024-11-20

Abstract: 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 deacetylase6 (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 translocation2 (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.

DOI: 10.1038/s41586-024-08248-5

Source: https://www.nature.com/articles/s41586-024-08248-5