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Updated: Jun 27, 2025

Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
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Published on: March 5, 2019

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

Peng Li1,2,3, Xiaochen Gai1,2,3, Qilin Li1,2,3

  • 1Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.

Nucleic Acids Research
|April 29, 2024
PubMed

Insights

Low doses of DNA-PK inhibitors and PARP inhibitors suppress BRCA-deficient tumors by targeting nucleolar function, not DNA damage. This reveals a novel DNA damage repair-independent mechanism for DNA-PK inhibitors in cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • DNA-PK inhibitors (DNA-PK-i) are used in cancer clinical trials, but their tumor suppression mechanisms and biomarkers are not fully understood.
  • The role of DNA-PK in DNA damage repair is established, but non-canonical functions are emerging.

Purpose of the Study:

  • To elucidate the mechanism of action for DNA-PK inhibitors in tumor cell suppression.
  • To investigate the interplay between DNA-PK inhibitors and PARP inhibitors in BRCA-deficient cancers.

Main Methods:

  • Utilized low-dose DNA-PK inhibitors and PARP inhibitors in BRCA-deficient tumor models.
  • Investigated DNA double-strand breaks (DSBs) and DNA-PK localization.
  • Analyzed DNA-PKcs and ribosomal protein phosphorylation.
  • Assessed pre-ribosomal RNA (rRNA) biogenesis and tumor cell growth.

Main Results:

  • Combined low-dose DNA-PK-i and PARP-i synergistically suppressed BRCA-deficient tumor cells without inducing DSBs.
  • DNA-PK was found in nucleoli, where Ku proteins recognize pre-rRNA, promoting DNA-PKcs autophosphorylation independently of DNA damage.
  • DNA-PK phosphorylates ribosomal proteins, regulating pre-rRNA biogenesis.
  • Inhibition of DNA-PK and PARP suppressed pre-rRNA biogenesis and tumor cell proliferation.

Conclusions:

  • DNA-PK inhibitors possess a DNA damage repair-independent role in tumor suppression.
  • Targeting nucleolar function via DNA-PK and PARP inhibition offers a novel therapeutic strategy for BRCA-deficient cancers.

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