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ANP32E drives vulnerability to ATR inhibitors by inducing R-loops-dependent transcription replication conflicts in

Sara Lago1, Vittoria Poli1, Lisa Fol1,2

  • 1Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123, Trento, Italy.

Nature Communications
|May 17, 2025
PubMed

Insights

Chromatin regulator ANP32E exacerbates cancer genomic instability by promoting transcription-replication conflicts and R-loop accumulation. Inhibiting the ATR DNA damage response pathway shows promise for treating ANP32E-overexpressing tumors.

Area of Science:

  • Molecular Oncology
  • Cancer Genomics
  • Chromatin Biology

Background:

  • Oncogene-induced replicative stress (RS) disrupts genome stability via transcription-replication conflicts (TRCs).
  • TRCs promote R-loop accumulation and trigger the DNA damage response (DDR), contributing to tumor progression.
  • Chromatin regulators are implicated in exacerbating TRCs and R-loop formation in cancer.

Purpose of the Study:

  • To investigate the role of chromatin regulators in TRC and R-loop exacerbation in cancer.
  • To explore the correlation between MYC, ANP32E, and genomic instability in breast cancer.
  • To identify potential therapeutic strategies targeting ANP32E-driven genomic fragility.

Main Methods:

  • Genome-wide analyses to assess ANP32E's impact on H2A.Z turnover and RNA polymerase II processivity.
  • Investigation of ANP32E's role in TRC formation and ATR-dependent DDR activation.
  • Evaluation of ATR inhibitor efficacy in ANP32E-overexpressing cancer cells.

Main Results:

  • Simultaneous upregulation of MYC and ANP32E correlates with increased genomic instability in breast cancer patients.
  • ANP32E-driven H2A.Z turnover leads to long R-loop accumulation at TRC sites.
  • ANP32E overexpression enhances TRC formation, activates ATR-DDR, and promotes R-loop-mediated genomic fragility.
  • ANP32E-expressing tumors are vulnerable to ATR inhibitors, with inhibition halting pro-metastatic capacity.

Conclusions:

  • ANP32E is a key driver of TRC-induced genomic instability in cancer.
  • ATR inhibition represents a potential therapeutic strategy for ANP32E-overexpressing tumors.
  • Targeting ANP32E and the ATR pathway could offer new avenues for cancer treatment.

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