匹兹堡大学医学院Katherine M. Aird团队取得一项新突破。他们研究出αKG介导的肉碱合成通过组蛋白乙酰化驱动DNA修复。相关论文发表在2026年5月27日出版的《自然》杂志上。

在这里，研究组发现α-酮戊二酸（αKG）的消耗通过代谢调节组蛋白乙酰化使HR精通细胞对DNA损伤剂敏感。αKG是αKG依赖性双加氧酶2 （αKGDDs）活性的必需条件，以往的研究几乎都集中在αKGDD的去甲基化酶功能上。利用由64个αKGDDs组成的靶向CRISPR敲除文库，该研究团队发现三甲基赖氨酸羟化酶ε （TMLHE）是重新合成肉毒碱的第一酶和限速酶，是在DNA损伤剂存在下HR精通细胞存活所必需的。

出乎意料的是，αKG介导的TMLHE依赖性肉毒碱合成是组蛋白乙酰化所必需的，并且与其他核胞浆乙酰辅酶A生成途径没有冗余。通过αKG -肉碱轴增加组蛋白乙酰化，通过位点特异性组蛋白乙酰化促进HR介导的DNA修复。最后，该研究组在患者样本中观察到TMLHE与组蛋白乙酰化之间的正相关，并发现高TMLHE或乙酰肉碱与接受DNA损伤药物治疗的患者更差的无进展生存相关。据他们所知，这项研究首次证明了αKG影响位点特异性组蛋白乙酰化，并提供了通过肉碱合成HR熟练的机制。

此外，这些数据为诱导HR缺乏和促进对DNA损伤剂的敏感性提供了代谢途径。

研究人员表示，同源重组（HR）缺陷增加了对通常用于治疗癌症的DNA损伤剂的敏感性。在HR功能正常的癌症中，驱动对DNA损伤剂的反应或抵抗的代谢机制尚不清楚。

附：英文原文

Title: αKG-mediated carnitine synthesis drives DNA repair via histone acetylation

Author: Uboveja, Apoorva, Yang, Baixue, Buj, Raquel, Amalric, Amandine, Wang, Hui, Tangudu, Naveen Kumar, Cole, Aidan R., Disharoon, Julie A., Fang, Richard S., Levasseur, Evan, Naruse, Miho, Huang, Zhentai, Megill, Emily, Kantner, Daniel S., Chatoff, Adam, Ahmad, Hafsah, Marcinkiewicz, Mariola M., Graff, Sarah, De Pieri, Ellen, Huacachino, Andrea Andress, Vendetti, Frank P., Danielson, Jeff, Dahl, Erika S., Pennise, Jennifer L., Elishaev, Esther, Jaccard, Alison, Borho, Lauren, Post, Miriam D., Cooper, Kristine, Modugno, Francesmary, Hempel, Nadine, Stallaert, Wayne, Bakkenist, Christopher J., Sidoli, Simone, Wellen, Kathryn E., Bitler, Benjamin G., Long, David T., Snyder, Nathaniel W., Aird, Katherine M.

Issue&Volume: 2026-05-27

Abstract: Homologous recombination (HR) deficiency increases sensitivity to DNA-damaging agents that are commonly used to treat cancer1. In HR-proficient cancers, the metabolic mechanisms that drive response or resistance to DNA-damaging agents remain unclear. Here we have identified that depletion of α-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA-damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases2 (αKGDDs), and previous work has focused almost exclusively on the demethylase functions of αKGDD. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that trimethyllysine hydroxylase epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for the survival of HR-proficient cells in the presence of DNA-damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation and was non-redundant with other nucleo-cytosolic acetyl-CoA-generating pathways. The increase in histone acetylation by means of the αKG–carnitine axis promoted HR-mediated DNA repair through site-specific histone acetylation. Finally, we observed a positive correlation between TMLHE and histone acetylation in patient samples and found that high TMLHE or acetylcarnitine correlates with worse progression-free survival in patients treated with DNA-damaging agents. This study demonstrates for the first time, to our knowledge, that αKG affects site-specific histone acetylation and provides a mechanism of HR proficiency through carnitine synthesis. Moreover, these data provide a metabolic avenue for inducing HR deficiency and promoting sensitivity to DNA-damaging agents.

DOI: 10.1038/s41586-026-10584-7

Source: https://www.nature.com/articles/s41586-026-10584-7