Article Dans Une Revue (Data Paper) Cancer Research Année : 2025

Replication-poison treatment in BRCA1-deficient breast cancer causes MRE11 over-resection that induces single-stranded DNA accumulation and Mitotic Catastrophe

Cyril Ribeyre

Résumé

BRCA1 deficiency is observed in approximately 25% of triple-negative breast cancer (TNBC). BRCA1, a key player of homologous recombination (HR) repair, is also involved in stalled DNA replication fork protection and repair. Here, we investigated the sensitivity of BRCA1-deficient TNBC models to the frequently used replication chain terminator gemcitabine, which does not directly induce DNA breaks. A large fraction of BRCA1-deficient cells was sensitive to gemcitabine, in contrast to their isogenic BRCA1-proficient counterparts. Gemcitabine treated BRCA1-deficient cells accumulated massive levels of single strand DNA (ssDNA) and presented no RPA or RAD51 nuclear foci. The gemcitabine-induced accumulation of ssDNA in BRCA1-deficient cells was strongly diminished by targeting MRE11 with inhibitors and by siRNA attenuation. In contrast, treatment with the PARP1/2 inhibitor olaparib did not result in MRE11 dependent over-resection. Furthermore, a fraction of gemcitabine treated BRCA1-deficient cells that showed massive ssDNA accumulation slipped into mitosis, producing mitotic bridges and strongly stained BrdU and γH2AX micronuclei (MN). The BrdU-positive MN and DNA bridges also stained positively for cGAS. In conclusion, these data suggest that gemcitabine treatment in BRCA1-deficient TNBC exposes unprotected nascent DNA linked to replication fork reversal, which leads to MRE11 over-resection and ssDNA accumulation. Therefore, the observed hypersensitivity to gemcitabine indicates that it could be a beneficial addition to BRCA1-deficient TNBC treatment.

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hal-04931535 , version 1 (05-02-2025)

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Imene Tabet, Esin Orhan, Ermes Candiello, Lise Fenou, Carolina Velázquez, et al.. Replication-poison treatment in BRCA1-deficient breast cancer causes MRE11 over-resection that induces single-stranded DNA accumulation and Mitotic Catastrophe. Cancer Research, 2025, ⟨10.1158/0008-5472.CAN-24-1404⟩. ⟨hal-04931535⟩
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