NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance

Hengxing Chen, Yun Li, Huafu Li, Xiancong Chen, Huafeng Fu, Deli Mao, Wei Chen, Linxiang Lan, Chunming Wang, Kaishun Hu, Jia Li, Chengming Zhu, Ian Evans, Eddie Cheung, Daning Lu, Yulong He (), Axel Behrens (), Dong Yin () and Changhua Zhang ()
Additional contact information
Hengxing Chen: The Seventh Affiliated Hospital of Sun Yat-sen University
Yun Li: Sun Yat-sen University
Huafu Li: The Institute of Cancer Research
Xiancong Chen: The Seventh Affiliated Hospital of Sun Yat-sen University
Huafeng Fu: The Seventh Affiliated Hospital of Sun Yat-sen University
Deli Mao: The Seventh Affiliated Hospital of Sun Yat-sen University
Wei Chen: The Seventh Affiliated Hospital of Sun Yat-sen University
Linxiang Lan: The Seventh Affiliated Hospital of Sun Yat-sen University
Chunming Wang: The Seventh Affiliated Hospital of Sun Yat-sen University
Kaishun Hu: Sun Yat-sen University
Jia Li: The Seventh Affiliated Hospital of Sun Yat-sen University
Chengming Zhu: The Seventh Affiliated Hospital of Sun Yat-sen University
Ian Evans: The Institute of Cancer Research
Eddie Cheung: The Seventh Affiliated Hospital of Sun Yat-sen University
Daning Lu: Sun Yat-sen University
Yulong He: The Seventh Affiliated Hospital of Sun Yat-sen University
Axel Behrens: The Institute of Cancer Research
Dong Yin: Sun Yat-sen University
Changhua Zhang: The Seventh Affiliated Hospital of Sun Yat-sen University

Nature, 2024, vol. 631, issue 8021, 663-669

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07620-9

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