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.