中山大学张常华等研究人员合作发现，NBS1乳酸化对于高效DNA修复和化疗耐药性至关重要。这一研究成果于2024年7月3日在线发表在国际学术期刊《自然》上。

研究人员报告，乳酸驱动的NBS1乳酸化促进了同源重组（HR）介导的DNA修复。NBS1在赖氨酸388（K388）处的乳酸化对于MRE11-RAD50-NBS1（MRN）复合物的形成以及HR修复蛋白在DNA双链断裂位点的积累至关重要。此外，研究人员鉴定了TIP60是NBS1赖氨酸乳酸转移酶，也是NBS1 K388乳酸化的“书写者”，而HDAC3是NBS1的去乳酸酶。

高水平的NBS1 K388乳酸化预示着新辅助化疗患者的不良预后，通过基因耗竭乳酸脱氢酶A（LDHA）或临床用于抗癫痫治疗的乳酸脱氢酶A抑制剂斯替仑（stiripentol）来减少乳酸，可抑制NBS1 K388乳酸化，降低DNA修复效率并克服化疗耐药性。总之，该工作确定了NBS1乳酸化作为基因组稳定性的关键机制，这有助于化疗耐药性，并将乳酸生成的抑制作为一种有前景的癌症治疗策略。

据悉，沃伯格效应是癌症的一个标志，指的是癌细胞偏好无氧代谢葡萄糖而非有氧代谢。这导致癌细胞内乳酸的显著积累，这是无氧糖酵解的最终产物。然而，癌症代谢如何影响化疗反应和DNA修复尚未完全理解。

附：英文原文

Title: NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance

Author: Chen, Hengxing, Li, Yun, Li, Huafu, Chen, Xiancong, Fu, Huafeng, Mao, Deli, Chen, Wei, Lan, Linxiang, Wang, Chunming, Hu, Kaishun, Li, Jia, Zhu, Chengming, Evans, Ian, Cheung, Eddie, Lu, Daning, He, Yulong, Behrens, Axel, Yin, Dong, Zhang, Changhua

Issue&Volume: 2024-07-03

Abstract: The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells3. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11–RAD50–NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the ‘writer’ of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.

DOI: 10.1038/s41586-024-07620-9

Source: https://www.nature.com/articles/s41586-024-07620-9