PDF(Pubmed)
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.
摘要：
Warburg效应是癌症的标志，是指癌细胞优先于厌氧代谢葡萄糖而不是需氧代谢1,2。这导致乳酸的大量积累，无氧糖酵解的最终产物，癌细胞3.然而,总体上,癌症代谢如何影响化疗反应和DNA修复仍未完全了解.在这里，我们报道了乳酸驱动的NBS1的乳酸化促进同源重组（HR）介导的DNA修复。NBS1在赖氨酸388（K388）的酰化对于MRE11-RAD50-NBS1（MRN）复合物的形成和HR修复蛋白在DNA双链断裂位点的积累至关重要。此外，我们将TIP60鉴定为NBS1赖氨酸乳酰转移酶和NBS1K388的“作者”，和HDAC3作为NBS1脱乳酶。高水平的NBS1K388乳酸化预测患者新辅助化疗的不良预后，使用乳酸脱氢酶A（LDHA）或stiripentol的遗传消耗来减少乳酸，乳酸脱氢酶一种临床上用于抗癫痫治疗的抑制剂，抑制NBS1K388的乳酸化，降低DNA修复功效，克服化疗耐药。总之,我们的工作确定NBS1的乳酸化作用是导致化疗耐药的基因组稳定性的关键机制,并确定抑制乳酸产生是一种有前景的癌症治疗策略.
