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

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 and Alessio Zippo ()
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Sara Lago: University of Trento
Vittoria Poli: University of Trento
Lisa Fol: University of Trento
Mattia Botteon: University of Trento
Federica Busi: University of Trento
Alice Turdo: University of Palermo
Miriam Gaggianesi: University of Palermo
Yari Ciani: University of Trento
Giacomo D’Amato: University of Trento
Luca Fagnocchi: University of Trento
Alessandra Fasciani: University of Trento
Francesca Demichelis: University of Trento
Matilde Todaro: University of Palermo
Alessio Zippo: University of Trento

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59804-0

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