Commentary

Published: 22 January 2024

Hui Yang, Jinqin Qian, Xiaopeng Lu & Wei-Guo Zhu 

Genome Instability & Disease Volume 5, pages 45–47, (2024)

The Warburg effect, first proposed by Otto Warburg in the 1920s, revealed the preference of cancer cells to utilize glycolysis instead of aerobic respiration, even in an environment with sufficient oxygen (Hsu & Sabatini, 2008). Due to the complexity of cellular metabolism, the mechanisms of the Warburg effect in the tumor microenvironment are still poorly understood. In 2019, an interesting finding was reported that accumulated lactate in tumor microenvironment promotes the lactylation of histone lysine residues, regulating gene expression and inflammatory response (Zhang et al., 2019). This study brought lactylation, a novel type of post-translational modification (PTM), into the spotlight. Afterwards, investigations about histone lactylation sprang up and suggested diverse functions of histone lactylation in cell reprogramming (Li et al., 2020), inflammatory metabolic adaptation (Dichtl, et al., 2021), Alzheimer's disease (Pan, et al., 2022) and tumorigenesis (Yang et al., 2023; Yu et al., 2021). In addition to histones, other studies also found this modification on non-histone proteins and its promotion of metabolic reprogramming as well as malignancy progression in tumors (Sun et al., 2023; Yang et al., 2023). It is widely recognized that protein lactylation plays pivotal roles in tumorigenesis, and only a small part of this modification was dug up, leaving many mysteries to be explored.

Constantly threatened by endogenous metabolites and genotoxic stresses, organisms have evolved refined DNA repair systems to safeguard genome integrity. DNA double-strand breaks (DSBs) are the most harmful forms of DNA lesions that are typically repaired by two main pathways: non-homologous end joining (NHEJ) and homologous recombination (HR) (Groelly et al., 2023). Whether and how DNA damage repair can be regulated by Warburg effect is a quite interesting question and has not been well answered. Recently Chen and colleagues published a comprehensive research article entitled “Metabolic regulation of homologous recombination repair by MRE11 lactylation” in Cell (Chen et al., 2023). This study unveils, for the first time, that lactate metabolism is tied up to DSBs repair and the impact of the Warburg effect on chemoresistance.

By analyzing the data in TCGA database, Chen et al. found that high levels of lactate or protein lactylation might exert a pivotal function in HR repair. This theory was supported by the finding that supplementation of sodium lactate in cancer cells improved the repair of damaged DNA after irradiation. Consistently and attractively, the L-lactate dehydrogenase A (LDHA) inhibitor significantly impaired HR repair and enhanced the cytotoxicity of chemotherapy drugs such as etoposide, cisplatin and olaparib on tumor cells. These findings revealed an intrinsic connection between lactate metabolism and DNA damage repair, providing a new insight into dealing with tumor chemoresistance.

Homologous recombination (HR) repair is a tightly controlled molecular mechanism, primarily utilizing sister chromatids for error-free DSB repair (Groelly et al., 2023). By screening key proteins in HR repair pathway, MRE11 was found to be lactylated at K673 under DNA damage conditions. MRE11 is a core component of the multifunctional MRE11-RAD50-NBS1 (MRN) complex that detects DNA double-strand breaks (DSBs), activates the ATM checkpoint kinase, and initiates homologous recombination (HR) repair of DSBs (Williams et al., 2008). Furthermore, the authors investigated the “Writer” and “Eraser” of MRE11 lactylation and found that it is primarily mediated by the CBP transferase, with SIRT1 and SIRT2 functioning as “Erasers”.

DNA end resection by MRE11 is a critical step in the HR repair pathway (Zhao et al., 2020). MRE11 K673 lactylation can enhance its DNA binding ability, promoting DNA end resection and HR repair. It is worth mentioning that previous studies have demonstrated various post-translational modifications of MRE11, such as phosphorylation, ubiquitination, and methylation, which participate in the regulation of MRE11 activities in DNA damage recognition, DNA binding, nuclease activity, and signal transduction (Kanaar & Wyman, 2008). Previous findings suggested a potential ubiquitination at the MRE11 K673 site (Jachimowicz, et al., 2019; Wagner, et al., 2011). The role of MRE11 K673 lactylation on DNA end resection was further strengthened by investigating the K673R mutant on MRE11 ubiquitination and stability. Additionally, the potential impact of MRE11 K673 acetylation was also ruled out by studying the acetyltransferase GCN5-mediated MRE11 K673 acetylation.

Considering that highly active homologous recombination repair may lead to tumor resistance to chemotherapy drugs, Chen et al. explored the impact of MRE11 K673 lactylation on platinum-based or PARP inhibitor chemotherapy drugs. The results showed that tumors with high MRE11 K673 lactylation were resistant to chemotherapy drugs, while inhibiting MRE11 K673 lactylation enhanced the efficacy of chemotherapy drugs. Meaningfully, Chen et al. developed small peptides specifically inhibiting MRE11 K673 lactylation, which significantly enhanced the cytotoxic effects of platinum-based or PARP inhibitor chemotherapy on tumors with PDX models. These results strongly indicate that targeted inhibition of MRE11 K673 lactylation can enhance the efficacy of chemotherapy.

In summary, this study demonstrated the important role of MRE11 lactylation in HR repair, and targeting the lactylation of MRE11 may be an effective strategy to overcome cancer resistance to therapeutic drugs. Chen et al. uncovered a direct link between tumor cell metabolism and homologous recombination repair, giving a convinced answer to “what does the Warburg effect do in cancer chemoresistance”.