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TitleLactylation of XLF promotes non-homologous end-joining repair and chemoresistance in cancer.
Journal, issue, pagesMol Cell, Vol. 85, Issue 14, Page 2654-22672.e7, Year 2025
Publish dateJul 17, 2025
AuthorsMingpeng Jin / Bingsong Huang / Xiaoning Yang / Shuyang Wang / Jinhuan Wu / Yiming He / Xin Ding / Xuanhe Wang / Zhe Wang / Jie Yang / Rui Li / Xuan Zhou / Qianwen Wang / Yunhui Li / Lei Li / Wen Zheng / Zhikai Zeng / Chenxi Zhao / Jiaqi Liu / Qian Zhu / Zhihua Kang / Ke Li / Shikang Liang / Yuping Chen / Jian Yuan /
PubMed AbstractMetabolic reprogramming and DNA damage repair are essential in tumorigenesis and chemoresistance, yet their link remains elusive. Here, we show that LDHA deficiency impairs NHEJ and class switch ...Metabolic reprogramming and DNA damage repair are essential in tumorigenesis and chemoresistance, yet their link remains elusive. Here, we show that LDHA deficiency impairs NHEJ and class switch recombination. Additionally, glycolysis-derived lactate promotes XLF lactylation at K288 within its Ku-binding motif (X-KBM) to regulate NHEJ. Mechanistically, DNA damage triggers ATM-mediated GCN5 phosphorylation to increase GCN5-XLF interaction and XLF lactylation, enhancing XLF-Ku80 binding, XLF recruitment to DSBs, and NHEJ efficiency. Cryo-EM structural analysis demonstrates that lactylated X-KBM (laX-KBM) forms a more extensive interface with Ku70/80, inducing conformational changes in the Ku80 vWA domain. XLF lactylation deficiency impairs NHEJ and sensitizes cancer cells to chemotherapy. A specific XLF K288 lactylation peptide inhibitor plus 5-fluorouracil synergistically kills colorectal cancer cells in PDX models with XLF hyperlactylation. These findings highlight that the GCN5-XLF lactylation axis is a critical NHEJ regulator and that targeting XLF lactylation can improve chemotherapy efficiency.
External linksMol Cell / PubMed:40680721
MethodsEM (single particle)
Resolution3.46 Å
Structure data

60744

9iol

EMDB-60744, PDB-9iol:
Cryo-EM structure of the complex of DNA, Ku70/80, and laXLF.
Method: EM (single particle) / Resolution: 3.46 Å

Chemicals

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE

ChemComp-2OP:
(2S)-2-HYDROXYPROPANOIC ACID

Source
  • homo sapiens (human)
KeywordsDNA BINDING PROTEIN/DNA / DNA repair / NHEJ / Complex / Lactylation / DNA BINDING PROTEIN / DNA BINDING PROTEIN-DNA complex

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