Genomic instability caused by abnormal response to DNA damage is one of the basic molecular biological characteristics of malignant transformation from normal cells to tumor cells. Metabolic reprogramming is also an important molecular biological feature driving tumorigenesis. So does metabolic reprogramming synergistically mediate tumorigenesis and development with dysregulation of DNA damage response?A significant feature of tumor metabolic reprogramming is the excessive accumulation of metabolites such as lactate and adenosylmethionine in tumor cells and tumor microenvironment. In addition to being the energy base to promote tumorigenesis and development, these metabolites can also be used as donors of protein post-translational modifications to regulate tumor signaling pathways. December 20, 2023, East Hospital, Tongji University School of Medicine, ShanghaiYuan JianThe professor's research group is incellpublished a post entitledmetabolic regulation of homologous recombination repair by mre11 lactylationof the results of the research,The key molecular mechanism of protein lactation modification linking tumor metabolism and DNA damage repair was revealed, and potential tumor targets and strategies were provided. 
The research team first discovered an association between tumor metabolic reprogramming and homologous recombination repair from the TCGA database, in particular:Lactate dehydrogenaseldha) is associated with down-regulation of homologous recombination repair in this process. They further confirmed that lactation modification is involved in homologous recombination repair, and found that sodium lactate treatment can promote cellular panlactic acidification level and homologous recombination repair, but does not increase intracellular lactate level. LDH inhibitors can significantly inhibit homologous recombination repair and enhance the killing effect of chemotherapy drugs on tumor cells, which preliminarily proves the role of protein lactation modification in homologous recombination repair. At the molecular level, the research team screened several key homologous recombination repair regulatory proteins and found that MRE11, a nuclease that plays an important regulatory role in initiating DNA end cleavage and homologous recombination repair, has the strongest level of lactation modification. Further experimental results showed that the lactation modification of MRE11 K673 promoted the binding of MRE11 to DNA, which in turn promoted DNA end cleavage and homologous recombination repair. Inhibition or deletion mutations in the lactation of MRE11 K673 significantly inhibit the DNA repair process. Highly active homologous recombination repair often leads to tumor resistance to chemotherapeutic agents, and the research team further explored the effect of MRE11 K673 lactated modification status on platinum or PARP inhibitor chemotherapeutic agents. The results showed that tumors with high MRE11 K673 lactation were resistant to chemotherapy drugs, and inhibition of MRE11 K673 lactation could enhance the efficacy of chemotherapy drugs. In order to further specifically inhibit the lactation of MRE11 K673 to kill tumors, they designed and screened a small molecule polypeptide that could specifically inhibit the lactation of MRE11 K673, and found that the peptide could significantly improve the killing effect of platinum or PARP inhibitor chemotherapy on tumors in cells and in vivo PDX models. These results suggest that targeted inhibition of the lactation modification of MRE11 K673 is a potential strategy to improve the efficacy of chemotherapy. In summary, this studyIt reveals the key molecular links and biological basis between cellular metabolism and homologous recombination repair, and provides a new theoretical basis and potential targets for targeted DNA repair to overcome tumor drug resistance. 
Professor Yuan Jian is the corresponding author of this paper, and associate professor Chen Yuping and postdoctoral fellow Wu Jinhuan of Tongji University are the co-first authors of this paper. This project has developed good cooperation with the research group of Prof. Tan Minjia of the Institute of Materia Medica, Shanghai Chinese Academy of Sciences, the research group of Prof. Ke Li of the Institute of Pharmaceutical Biotechnology of the Chinese Academy of Medical Sciences and Peking Union Medical College, the research group of Prof. Wang Jiadong and Prof. Wang Weibin of Peking University, the research group of Prof. Zhu Weiguo and Prof. Xu Xingzhi of Shenzhen University. Professor Jian Yuan's team has long focused on DNA damage and tumor research, and is committed to exploring the association between tumor metabolic abnormalities and DNA damage repair. The team is actively recruiting postdoctoral fellows who are interested in DNA damage and tumor research, providing preferential treatment and comprehensive protection. Interested parties can submit their resumes. Resume delivery(If you are interested, please send your resume and other materials to): 100 Families Help ProgramOriginal link: