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The VCP/p97 segregase is a member of the AAA+ ATPase family that participates in numerous cellular processes including extraction of XPC from UV-induced DNA lesions during nucleotide excision repair. In this study, it was shown for the first time that BTG3-mediated CHK1 activation and phosphorylation of VCP/p97 at Ser775 govern the cytoplasm-to-nucleus shuttling of VCP/p97. Loss of BTG3 or CHK1 inhibition led to retention of VCP/p97 in the cytoplasm, thus delaying the extraction of lesion-bound XPC and hampering the repair of UV DNA lesions, which culminate in an increase in mutation and carcinogenesis in vivo. These findings not only reveal the molecular basis of VCP/p97 cytoplasm-to-nucleus shuttling but also highlight a potential role of BTG3 and CHK1 in guarding against UV-induced skin mutation and carcinogenesis.

The study, conducted by Dr. Sheau-Yann Shieh’s team in the Institute of Biomedical Sciences, Academia Sinica and funded by Academia Sinica and NSTC, was published on July 8, 2025 in the prominent journal Nucleic Acids Research.