DNA-PK participates in pre-rRNA biogenesis independent of DNA double-strand break repair.

Peng Li, Xiaochen Gai, Qilin Li, Qianqian Yang, Xiaochun Yu

Nucleic acids research 2024 Jun 24

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Although DNA-PK inhibitors (DNA-PK-i) have been applied in clinical trials for cancer treatment, the biomarkers and mechanism of action of DNA-PK-i in tumor cell suppression remain unclear. Here, we observed that a low dose of DNA-PK-i and PARP inhibitor (PARP-i) synthetically suppresses BRCA-deficient tumor cells without inducing DNA double-strand breaks (DSBs). Instead, we found that a fraction of DNA-PK localized inside of nucleoli, where we did not observe obvious DSBs. Moreover, the Ku proteins recognize pre-rRNA that facilitates DNA-PKcs autophosphorylation independent of DNA damage. Ribosomal proteins are also phosphorylated by DNA-PK, which regulates pre-rRNA biogenesis. In addition, DNA-PK-i acts together with PARP-i to suppress pre-rRNA biogenesis and tumor cell growth. Collectively, our studies reveal a DNA damage repair-independent role of DNA-PK-i in tumor suppression. © The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.

Citation

Peng Li, Xiaochen Gai, Qilin Li, Qianqian Yang, Xiaochun Yu. DNA-PK participates in pre-rRNA biogenesis independent of DNA double-strand break repair. Nucleic acids research. 2024 Jun 24;52(11):6360-6375