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Updated: Sep 18, 2025

Examination of Proteins Bound to Nascent DNA in Mammalian Cells Using BrdU-ChIP-Slot-Western Technique
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The DNA-PKcs/JNK/p53 pathway underlies changes in cell fate decision toward death during DNA replication catastrophe

Jinal A Patel1, Julie Rageul1, Natalie Lo1

  • 1Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, United States.

Nucleic Acids Research
|June 25, 2025
PubMed

Insights

Targeting cancer cell DNA replication with ATR inhibitors can trigger replication catastrophe, a form of cell death. This strategy diverts therapy-induced senescent cells toward apoptosis, enhancing anti-cancer therapy efficacy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • Cancer therapy often faces limitations due to therapy-induced senescence, which can negatively impact patient outcomes.
  • Exacerbating DNA replication stress in cancer cells is a potential therapeutic strategy.

Purpose of the Study:

  • To investigate a novel therapeutic strategy combining acute replisome dysfunction with Ataxia telangiectasia and Rad3-related (ATR) inhibition.
  • To divert senescent cancer cells towards cell death by inducing replication catastrophe.

Main Methods:

  • Utilized RNA-sequencing to identify p53-responsive genes involved in cell death.
  • Investigated the role of c-Jun N-terminal kinase (JNK) in p53-dependent apoptosis and γH2AX distribution.
  • Elucidated the signaling cascade involving DNA-PKcs, CHK1, MRE11, and PARP1 in replication catastrophe.

Main Results:

  • Identified a distinct set of p53-responsive genes critical for inducing cell death.
  • Demonstrated that JNK activation forms a feed-forward loop with p53 to drive apoptosis and γH2AX pan-nuclear distribution.
  • Established that DNA-PKcs activation initiates replication catastrophe signaling, involving MRE11 and PARP1 in recognizing single-stranded DNA gaps.

Conclusions:

  • The study elucidates the DNA-PKcs/JNK/p53 signaling axis regulating cell fate decisions between senescence and death.
  • Replication catastrophe, driven by specific signaling pathways, represents a targetable vulnerability in cancer therapy.
  • This approach holds potential for limiting senescent cell populations and improving anti-cancer treatment efficacy.

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