9IOL

Cryo-EM structure of the complex of DNA, Ku70/80, and laXLF.

9IOL の概要

• エントリーDOI: 10.2210/pdb9iol/pdb
• EMDBエントリー: 60744
• 分子名称: X-ray repair cross-complementing protein 5, X-ray repair cross-complementing protein 6, DNA (5'-D(P*CP*GP*CP*TP*GP*CP*CP*GP*AP*TP*TP*CP*GP*TP*CP*GP*AP*CP*CP*T)-3'), ... (7 entities in total)
• 機能のキーワード: dna repair, nhej, complex, lactylation, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 169170.58

構造登録者

Liang, S. (登録日: 2024-07-09, 公開日: 2025-07-09, 最終更新日: 2025-07-30)

主引用文献

Jin, M.,Huang, B.,Yang, X.,Wang, S.,Wu, J.,He, Y.,Ding, X.,Wang, X.,Wang, Z.,Yang, J.,Li, R.,Zhou, X.,Wang, Q.,Li, Y.,Li, L.,Zheng, W.,Zeng, Z.,Zhao, C.,Liu, J.,Zhu, Q.,Kang, Z.,Li, K.,Liang, S.,Chen, Y.,Yuan, J.
Lactylation of XLF promotes non-homologous end-joining repair and chemoresistance in cancer.
Mol.Cell, 85:2654-2672.e7, 2025

PubMed Abstract: 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.

PubMed: 40680721
DOI: 10.1016/j.molcel.2025.06.019

実験手法

ELECTRON MICROSCOPY (3.46 Å)