A3A induces DNA replication stress through PrimPol-mediated ssDNA gaps, creating a therapeutic vulnerability to gap-targeted DNA repair inhibitors. APOBEC3A (A3A) is a cytidine deaminase that contributes to mutagenesis in various cancers. A3A expression leads to DNA replication stress by inducing ssDNA gaps through PrimPol, which are repaired via ATR, RAD51, and translesion synthesis (TLS) pathways. Inhibition of ATR or PARP traps PARP on DNA, impairing repair and preferentially killing A3A-expressing cells. A3A-induced ssDNA gaps are repaired by ATR and RAD51, but not by Chk1. A3A-expressing cells are sensitive to PARP inhibitors and TLS inhibitors, and the combination of ATR and PARP inhibitors synergistically kills A3A-expressing cells. A3A-induced ssDNA gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-induced gaps are also repaired by TLS, but TLS is a minor contributor. A3A-induced gaps can be made persistent by PARP trapping, leading to DNA double-strand breaks (DSBs) and cell death. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR andA3A induces DNA replication stress through PrimPol-mediated ssDNA gaps, creating a therapeutic vulnerability to gap-targeted DNA repair inhibitors. APOBEC3A (A3A) is a cytidine deaminase that contributes to mutagenesis in various cancers. A3A expression leads to DNA replication stress by inducing ssDNA gaps through PrimPol, which are repaired via ATR, RAD51, and translesion synthesis (TLS) pathways. Inhibition of ATR or PARP traps PARP on DNA, impairing repair and preferentially killing A3A-expressing cells. A3A-induced ssDNA gaps are repaired by ATR and RAD51, but not by Chk1. A3A-expressing cells are sensitive to PARP inhibitors and TLS inhibitors, and the combination of ATR and PARP inhibitors synergistically kills A3A-expressing cells. A3A-induced ssDNA gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-induced gaps are also repaired by TLS, but TLS is a minor contributor. A3A-induced gaps can be made persistent by PARP trapping, leading to DNA double-strand breaks (DSBs) and cell death. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and RAD51, and the repair is epistatic. A3A-expressing cells are sensitive to ATR and PARP inhibitors, and the combination of these inhibitors is synergistic. A3A-induced gaps are repaired by ATR and