2. Academic Validation
  3. Metabolic regulation of homologous recombination repair by MRE11 lactylation

Metabolic regulation of homologous recombination repair by MRE11 lactylation

  • Cell. 2023 Dec 18:S0092-8674(23)01276-X. doi: 10.1016/j.cell.2023.11.022.
Yuping Chen 1,  Jinhuan Wu 1,  Linhui Zhai 2,  Tingting Zhang 3,  Hui Yin 4,  Huanyao Gao 5,  Fei Zhao 6,  Zhe Wang 1,  Xiaoning Yang 7,  Mingpeng Jin 1,  Bingsong Huang 1,  Xin Ding 1,  Rui Li 1,  Jie Yang 8,  Yiming He 1,  Qianwen Wang 1,  Weibin Wang 9,  Jake A Kloeber 10,  Yunxuan Li 3,  Bingbing Hao 2,  Yuanyuan Zhang 11,  Jiadong Wang 9,  Minjia Tan 2,  Ke Li 3,  Ping Wang 12,  Zhenkun Lou 13,  Jian Yuan 14
Affiliations

Affiliations

  • 1 State Key Laboratory of Cardiology and Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200120, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 4 Department of Thoracic Surgery, The First Affiliated Hospital of Shaoyang University, Shaoyang 422001, China.
  • 5 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
  • 6 Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 7 Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 8 Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
  • 9 Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 10 Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Medical Scientist Training Program, Mayo Clinic Alix School of Medicine and Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA.
  • 11 State Key Laboratory of Cardiology and Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
  • 12 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Shanghai 200072, China.
  • 13 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA; Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 14 State Key Laboratory of Cardiology and Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: yuanjian229@hotmail.com.
PMID: 38128537 DOI: 10.1016/j.cell.2023.11.022
Abstract

Lactylation is a lactate-induced post-translational modification best known for its roles in epigenetic regulation. Herein, we demonstrate that MRE11, a crucial homologous recombination (HR) protein, is lactylated at K673 by the CBP acetyltransferase in response to DNA damage and dependent on ATM phosphorylation of the latter. MRE11 lactylation promotes its binding to DNA, facilitating DNA end resection and HR. Inhibition of CBP or LDH downregulated MRE11 lactylation, impaired HR, and enhanced chemosensitivity of tumor cells in patient-derived xenograft and Organoid models. A cell-penetrating peptide that specifically blocks MRE11 lactylation inhibited HR and sensitized Cancer cells to cisplatin and PARPi. These findings unveil lactylation as a key regulator of HR, providing fresh insights into the ways in which cellular metabolism is linked to DSB repair. They also imply that the Warburg effect can confer chemoresistance through enhancing HR and suggest a potential therapeutic strategy of targeting MRE11 lactylation to mitigate the effects.

Keywords

CPP; MRE11; cell-penetrating peptide; chemoresistance; homologous recombination repair; lactylation; the Warburg effect.

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