Year: 2025
Type: article
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.
Source: Molecular Medicine
Authors: Luping Zhang, Yonghong Nie, Tuo Tang, Yanji Lu, Wenlong Li, Xian Hong, Qiang Li, Aixue Zheng, Yongpei Li, Jianwen Zhou, Li Fan, Tao Wang, Zhihui Deng
Institution: Qiqihar Medical University
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,190
Awards: G507327799, G8744163670
OpenAlex ID: W4411129050