Cheng Chen, McCauley Brenna S, Matulionis Nedas, Vogelauer Maria, Camacho Dimitrios, Christofk Heather R, Dang Weiwei, Irwin Nicholas A T, Kurdistani Siavash K
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Huffington Center on Aging, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Sci Adv. 2025 Apr 11;11(15):eadv4082. doi: 10.1126/sciadv.adv4082.
The discovery of histone H3 copper reductase activity provides a novel metabolic framework for understanding the functions of core histone residues, which, unlike N-terminal residues, have remained largely unexplored. We previously demonstrated that histone H3 cysteine 110 (H3C110) contributes to cupric (Cu) ion binding and its reduction to the cuprous (Cu) form. However, this residue is absent in , raising questions about its evolutionary and functional significance. Here, we report that H3C110 has been lost in many fungal lineages despite near-universal conservation across eukaryotes. Introduction of H3C110 into increased intracellular Cu levels and ameliorated the iron homeostasis defects caused by inactivation of the Cup1 metallothionein or glutathione depletion. Enhanced histone copper reductase activity also extended replicative life span under oxidative growth conditions but reduced it under fermentative conditions. Our findings suggest that a trade-off between histone copper reductase activity, iron metabolism, and life span may underlie the loss or retention of H3C110 across eukaryotes.
组蛋白H3铜还原酶活性的发现为理解核心组蛋白残基的功能提供了一个新的代谢框架，与N端残基不同，核心组蛋白残基在很大程度上仍未得到充分探索。我们之前证明，组蛋白H3半胱氨酸110（H3C110）有助于铜离子结合并将其还原为亚铜形式。然而，在……中不存在该残基，这引发了关于其进化和功能意义的问题。在这里，我们报告称，尽管H3C110在真核生物中几乎普遍保守，但在许多真菌谱系中已经丢失。将H3C110引入……可提高细胞内铜水平，并改善由Cup1金属硫蛋白失活或谷胱甘肽耗竭引起的铁稳态缺陷。增强的组蛋白铜还原酶活性在氧化生长条件下也延长了复制寿命，但在发酵条件下缩短了复制寿命。我们的研究结果表明，组蛋白铜还原酶活性、铁代谢和寿命之间的权衡可能是真核生物中H3C110丢失或保留的基础。
