Characterization of genetic modulators of PARP inhibitor sensitivity: molecular mechanisms and therapeutic implications

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The clinical success of PARP 1/2 inhibitors (PARPi) prompts the expansion of their applicability beyond homologous recombination deficiency. Here, we demonstrate that the loss of either the chromatin remodeler ALC1 or the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes cells to PARPi. We show that ALC1 is important for mobilizing PARP1 from sites of DNA damage. Upon ALC1 deletion, PARPi treatment leads to enhanced PARP1 trapping and accumulation of double-strand breaks, which underlies the sensitivity of ALC1 KO to PARPi. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Strikingly, targeting ALC1 could bypass PARPi resistance caused by restoration of homologous recombination. Furthermore, we demonstrate that POLE4 loss affects replication speed leading to the accumulation of single-stranded DNA gaps behind replication forks upon PARPi treatment, due to impaired post-replicative repair. POLE4 knockouts elicit elevated replication stress signaling involving ATR and DNA-PK. Importantly We find POLE4 to act parallel to BRCA1 in inducing sensitivity to PARPi and counteracts acquired resistance associated with restoration of homologous recombination. Altogether, our findings establish ALC1 and POLE4 as a promising target to improve PARPi driven therapies and hamper acquired PARPi resistance.

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