Poly(ADP-ribose) polymerase 1 (PARP1) is implicated in the detection and processing of unligated Okazaki fragments and other DNA replication intermediates, highlighting such structures as potential sources of genome breakage induced by PARP inhibition. Here, we show that PARP1 activity is greatly elevated in chicken and human S phase cells in which FEN1 nuclease is genetically deleted and is highest behind DNA replication forks. PARP inhibitor reduces the integrity of nascent DNA strands in both wild-type chicken and human cells during DNA replication, and does so in FEN1^−/− cells to an even greater extent that can be detected as postreplicative single-strand nicks or gaps. Collectively, these data show that PARP inhibitors impede the maturation of nascent DNA strands during DNA replication, and implicate unligated Okazaki fragments and other nascent strand discontinuities in the cytotoxicity of these compounds.

聚（ADP-核糖）聚合酶 1 (PARP1) 参与未连接的冈崎片段和其他 DNA 复制中间体的检测和处理，突出显示此类结构是 PARP 抑制诱导的基因组断裂的潜在来源。在这里，我们发现 PARP1 活性在 FEN1 核酸酶被基因删除的鸡和人 S 期细胞中显着升高，并且在 DNA 复制叉之后最高。 PARP 抑制剂在 DNA 复制过程中降低了野生型鸡和人类细胞中新生 DNA 链的完整性，并且在FEN1 ^{- / -}细胞中这种作用的程度甚至更大，可以通过复制后的单链切口或间隙来检测。总的来说，这些数据表明 PARP 抑制剂在 DNA 复制过程中阻碍新生 DNA 链的成熟，并暗示未连接的冈崎片段和其他新生链不连续性与这些化合物的细胞毒性有关。