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DNA2 protein destruction dictates DNA hyperexcision, cGAS-STING activation, and innate immune response in

Rui Sun1,2,3, Peng Jiang1, Zhijun Wang4

  • 1Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.

Proceedings of the National Academy of Sciences of the United States of America
|July 7, 2025
PubMed

Insights

CDK12 regulates DNA2 stability, impacting cancer cell genome integrity and immune response. Its inactivation triggers DNA damage and innate immunity, while amplification suppresses it, highlighting CDK12

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Immunology

Background:

  • CDK12 is a transcription regulatory kinase implicated in various cancers.
  • CDK12 mutations/deletions are found in prostate and ovarian cancers, while amplification occurs in breast cancer.

Purpose of the Study:

  • To investigate the role of CDK12 in DNA2 regulation and its downstream effects on cancer cells.
  • To elucidate the connection between CDK12, DNA2 stability, and the innate immune response.

Main Methods:

  • Investigated CDK12's effect on DNA2 phosphorylation and ubiquitination.
  • Analyzed gene expression changes in response to CDK12 inactivation or amplification.
  • Assessed replication stress, genomic instability, and cGAS-STING pathway activation.

Main Results:

  • CDK12 phosphorylates DNA2 at serine-933, promoting its degradation via APC/CCDC20.
  • CDK12 inactivation leads to DNA2 stabilization, replication stress, genomic instability, and cGAS-STING activation.
  • CDK12 amplification suppresses interferon response genes.

Conclusions:

  • DNA2 is a novel phosphorylation substrate of CDK12, linking CDK12 to cell cycle regulation.
  • CDK12-mediated DNA2 destruction is critical for preventing genomic instability and cGAS-STING signaling in cancer.
Keywords:
DNA resectioncGAS-STINGinnate immunityprostate cancerubiquitination

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