Nemzeti Gyógyszerkutatási és Fejlesztési Laboratórium (PharmaLab)(RRF-2.3.1-21-2022-00015)
Támogató: NKFIH
Mesterséges intelligencia alapú egysejt elemzés - alapkutatástól a betegágyig(TKP-31-8/PALY-2021)
Támogató: NKFI
The clinical success of PARP1/2 inhibitors (PARPi) prompts the expansion of their
applicability beyond homologous recombination deficiency. Here, we demonstrate that
the loss of the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes
cells to PARPi. We show that the sensitivity of POLE4 knockouts is not due to compromised
response to DNA damage or homologous recombination deficiency. Instead, 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.
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 POLE4 as a promising target to improve PARPi driven therapies
and hamper acquired PARPi resistance.