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Abstract:

Poly(ADP-ribose) polymerase inhibitors (PARPi) are used to treat individuals with inheritable cancers caused by mutations in the BRCA1 or BRCA2 genes that are required for DNA repair by homologous recombination (HR). PARPi’s exhibit strong efficacy in ovarian cancer but limited success in triple negative breast cancers (TNBC). Moreover, prolonged PARPi treatment is linked to hematologic toxicities, including myelosuppression, increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Using long-read sequencing we found that PARPi treatment caused high levels of structural variants (SVs), predominantly within centromeric regions. We also discovered a protective mechanism mediated by the MHF1-MHF2 complex, which recruits FANCM translocase to stabilize replication forks at centromeric repeats. MHF-defective cells were therefore hypersensitive to PARPi treatment. Surprisingly, centromeric replication fork instability which led to DNA breaks, mitotic catastrophe and cell inviability, was not caused by trapped PARP1, but was initiated by the removal of bound PARP1 by the FANCJ DNA helicase. MHF1-MHF2 is frequently amplified in TNBCs, and its inhibition selectively kills HR-deficient cells, offering a promising therapeutic strategy for TNBC beyond PARPi. These findings illuminate a critical link between centromeric DNA instability and PARPi response, highlighting implications for both hematologic toxicity and targeted cancer therapy.

By: Paula Amiet-West
Last updated: Monday, 9 February 2026