Journal Article

NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance

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

2024

Overview

The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically 1 , 2 . This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells 3 . 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. Lactylation of NBS1 by TIP60 promotes homologous recombination-driven DNA repair and resistance to chemotherapy in cancer cells and links altered cancer cell metabolism to increase genome stability.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/19 / 38/77 / 38/91 / 631/45/147 / 631/67/1059/99 / 82/1 / 82/51 / 82/58 / 96/106 / 96/109 / 96/63 / Accumulation / Acid Anhydride Hydrolases - metabolism / Anaerobiosis / Animals / Anticonvulsants - pharmacology / Cancer / Cancer therapies / Cell Cycle Proteins - chemistry / Cell Cycle Proteins - metabolism / Cell Line, Tumor / Chemoresistance / Chemotherapy / Complex formation / Dehydrogenase / Dehydrogenases / Deoxyribonucleic acid / Dioxolanes / DNA / DNA Breaks, Double-Stranded / DNA damage / DNA repair / DNA-Binding Proteins - metabolism / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Enzymes / Epilepsy / Female / Gastric cancer / Genomes / Genomic Instability / Glycolysis / Histone Deacetylase 3 / Homologous recombination / Humanities and Social Sciences / Humans / L-Lactate dehydrogenase / L-Lactate Dehydrogenase - antagonists & inhibitors / L-Lactate Dehydrogenase - deficiency / L-Lactate Dehydrogenase - genetics / L-Lactate Dehydrogenase - metabolism / Lactate dehydrogenase / Lactic acid / Lactic Acid - metabolism / Lysine / Lysine - chemistry / Lysine - metabolism / Lysine Acetyltransferase 5 - genetics / Lysine Acetyltransferase 5 - metabolism / Male / Metabolism / Metabolites / Mice / MRE11 Homologue Protein - metabolism / MRE11 protein / multidisciplinary / Neoadjuvant Therapy / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - metabolism / Nuclear Proteins - chemistry / Nuclear Proteins - metabolism / Organoids / Proteins / Proteomics / Recombinational DNA Repair / Science / Science (multidisciplinary) / Stiripentol / Tumors