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<p>Oncogene-induced replicative stress (RS) drives tumor progression by disrupting genome stability, primarily through transcription-replication conflicts (TRCs), which promote R-loop accumulation and trigger the DNA damage response (DDR). In this study, we investigate the role of chromatin regulators in exacerbating TRCs and R-loop accumulation in cancer. We find that in breast cancer patients, the simultaneous upregulation of MYC and the H2A.Z-specific chaperone ANP32E correlates with increased genomic instability. Genome-wide analyses reveal that ANP32E-driven H2A.Z turnover alters RNA polymerase II processivity, leading to the accumulation of long R-loops at TRC sites. Furthermore, we show that ANP32E overexpression enhances TRC formation and activates an ATR-dependent DDR, predisposing cancer cells to R-loop-mediated genomic fragility. By exploiting the vulnerability of ANP32E-expressing cancer cells to ATR inhibitors, we find that tumors relied on this DDR pathway, whose inhibition halts their pro-metastatic capacity. These findings identify ANP32E as a key driver of TRC-induced genomic instability, indicating ATR inhibition as a potential therapeutic strategy for ANP32E-overexpressing tumors.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月17日

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  • Sara Lago,
  • Vittoria Poli,
  • Lisa Fol,
  • Mattia Botteon,
  • Federica Busi,
  • Alice Turdo,
  • Miriam Gaggianesi,
  • Yari Ciani,
  • Giacomo D’Amato,
  • Luca Fagnocchi,
  • Alessandra Fasciani,
  • Francesca Demichelis,
  • Matilde Todaro,
  • Alessio Zippo

摘要

Oncogene-induced replicative stress (RS) drives tumor progression by disrupting genome stability, primarily through transcription-replication conflicts (TRCs), which promote R-loop accumulation and trigger the DNA damage response (DDR). In this study, we investigate the role of chromatin regulators in exacerbating TRCs and R-loop accumulation in cancer. We find that in breast cancer patients, the simultaneous upregulation of MYC and the H2A.Z-specific chaperone ANP32E correlates with increased genomic instability. Genome-wide analyses reveal that ANP32E-driven H2A.Z turnover alters RNA polymerase II processivity, leading to the accumulation of long R-loops at TRC sites. Furthermore, we show that ANP32E overexpression enhances TRC formation and activates an ATR-dependent DDR, predisposing cancer cells to R-loop-mediated genomic fragility. By exploiting the vulnerability of ANP32E-expressing cancer cells to ATR inhibitors, we find that tumors relied on this DDR pathway, whose inhibition halts their pro-metastatic capacity. These findings identify ANP32E as a key driver of TRC-induced genomic instability, indicating ATR inhibition as a potential therapeutic strategy for ANP32E-overexpressing tumors.