小柯机器人

同济大学医学院Jian Yuan团队近期取得重要工作进展，他们研究提出， MRE11的乳酸化修饰能调控DNA同源重组修复。相关研究成果2023年12月20日在线发表于《细胞》杂志上。

据介绍，乳酸化是一种乳酸诱导的翻译后修饰，以其在表观遗传学调控中的作用而闻名。

研究人员发现MRE11，一种关键的同源重组修复（HR）蛋白，在K673处被CBP乙酰转移酶乳基化，以响应DNA损伤。MRE11乳酸化促进其与DNA的结合，促进DNA末端切除和HR。在患者来源的异种移植物和类器官模型中，CBP或LDH的抑制下调了MRE11的乳酸化，损害了HR，并增强了肿瘤细胞的化学敏感性。特异性阻断MRE11乳酸化的细胞穿透肽抑制HR并使癌症细胞对顺铂和PARPi敏感。

总之，这一发现揭示了乳酸化是HR的关键调节因子，为细胞代谢与DSB修复的联系提供了新的见解。另外，研究结果还暗示Warburg效应可以通过增强HR来赋予化疗耐药，并提出了一种针对MRE11乳酸化的潜在治疗策略来减轻这种影响。

附：英文原文

Title: Metabolic regulation of homologous recombination repair by MRE11 lactylation

Author: Yuping Chen, Jinhuan Wu, Linhui Zhai, Tingting Zhang, Hui Yin, Huanyao Gao, Fei Zhao, Zhe Wang, Xiaoning Yang, Mingpeng Jin, Bingsong Huang, Xin Ding, Rui Li, Jie Yang, Yiming He, Qianwen Wang, Weibin Wang, Jake A. Kloeber, Yunxuan Li, Bingbing Hao, Yuanyuan Zhang, Jiadong Wang, Minjia Tan, Ke Li, Ping Wang, Zhenkun Lou, Jian Yuan

Issue&Volume: 2023-12-20

Abstract: Lactylation is a lactate-induced post-translational modification best known for itsroles in epigenetic regulation. Herein, we demonstrate that MRE11, a crucial homologousrecombination (HR) protein, is lactylated at K673 by the CBP acetyltransferase inresponse to DNA damage and dependent on ATM phosphorylation of the latter. MRE11 lactylationpromotes its binding to DNA, facilitating DNA end resection and HR. Inhibition ofCBP or LDH downregulated MRE11 lactylation, impaired HR, and enhanced chemosensitivityof tumor cells in patient-derived xenograft and organoid models. A cell-penetratingpeptide that specifically blocks MRE11 lactylation inhibited HR and sensitized cancercells to cisplatin and PARPi. These findings unveil lactylation as a key regulatorof HR, providing fresh insights into the ways in which cellular metabolism is linkedto DSB repair. They also imply that the Warburg effect can confer chemoresistancethrough enhancing HR and suggest a potential therapeutic strategy of targeting MRE11lactylation to mitigate the effects.

DOI: 10.1016/j.cell.2023.11.022

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01276-X