2. Academic Validation
  3. Nuclear VPS35 attenuates NHEJ repair by sequestering Ku protein

Nuclear VPS35 attenuates NHEJ repair by sequestering Ku protein

  • Mol Med. 2025 Jun 9;31(1):222. doi: 10.1186/s10020-025-01288-1.
Luping Zhang 1 2,  Yonghong Nie 1 2,  Tuo Tang 1 2,  Yanji Lu 1 2,  Wenlong Li 1 2,  Xian Hong 1,  Qiang Li 1 2,  Aixue Zheng 1 2,  Yongpei Li 1 2,  Jianwen Zhou 3,  Li Fan 3,  Tao Wang 4 5,  Zhihui Deng 6 7
Affiliations

Affiliations

  • 1 Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, China.
  • 2 Department of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, China.
  • 3 Laboratory of Molecular Biology, Institute of Medicine and Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, China.
  • 4 Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, China. wangtao@qmu.edu.cn.
  • 5 Department of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, China. wangtao@qmu.edu.cn.
  • 6 Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, China. deng.zhihui@qmu.edu.cn.
  • 7 Heilongjiang Provincial key Laboratory of Precise Diagnosis and Neuropsychological Regulation of Mental Disorders, Qiqihar, Heilongjiang, 161006, China. deng.zhihui@qmu.edu.cn.
PMID: 40484931 DOI: 10.1186/s10020-025-01288-1
Abstract

Vacuolar protein sorting-associated protein 35 (VPS35), a pivotal constituent of the retromer complex, mediates the retrograde trafficking of endosomal cargoes in the cytoplasm. Intriguingly, VPS35 displays a dual localization pattern, residing both in the cytoplasm and the nucleus, but its nuclear role remains elusive. In this study, we unravel a nuclear function of VPS35, demonstrating it impedes DNA repair by inhibiting non-homologous end joining (NHEJ). Mechanistically, VPS35 interacts with the Ku protein, sequestering it away from DNA damage sites. Consequently, nuclear VPS35 halts the activation of DNA-PKcs, hindering the recruitment of XLF and DNA-Ligase 4, ultimately suppressing NHEJ efficiency. Furthermore, in response to DNA damage, VPS35 dissociates from Ku protein and orchestrates a strategic relocation from the nucleus to the cytoplasm. Thus, our findings suggest VPS35 attenuates NHEJ repair by restricting Ku protein availability at DNA damage sites, offering a potential avenue for fine-tuning DNA repair efficiency.

Supplementary Information: The online version contains supplementary material available at 10.1186/s10020-025-01288-1.

Keywords

DNA repair; Ku; Non-homologous end joining; VPS35.

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