The antitumor activity of poly(ADP-ribose) polymerase inhibitors (PARPis) has been
ascribed to PARP trapping, which consists in tight DNA-protein complexes. Here we
demonstrate that the cytotoxicity of talazoparib and olaparib results from DNA replication.
To elucidate the repair of PARP1-DNA complexes associated with replication in human
TK6 and chicken DT40 lymphoblastoid cells, we explored the role of Spartan (SPRTN),
a metalloprotease associated with DNA replication, which removes proteins forming
DPCs. We find that SPRTN-deficient cells are hypersensitive to talazoparib and olaparib,
but not to veliparib, a weak PARP trapper. SPRTN-deficient cells exhibit delayed clearance
of trapped PARP1 and increased replication fork stalling upon talazoparib and olaparib
treatment. We also show that SPRTN interacts with PARP1 and forms nuclear foci that
colocalize with the replicative cell division cycle 45 protein (CDC45) in response
to talazoparib. Additionally, SPRTN is deubiquitinated and epistatic with translesion
synthesis (TLS) in response to talazoparib. Our results demonstrate that SPRTN is
recruited to trapped PARP1 in S-phase to assist in the excision and replication bypass
of PARP1-DNA complexes.
