Yang Yun-Gui, Cortes Ulrich, Patnaik Srinivas, Jasin Maria, Wang Zhao-Qi
International Agency for Research on Cancer, 150 cours Albert-Thomas, Lyon 69008, France.
Oncogene. 2004 May 6;23(21):3872-82. doi: 10.1038/sj.onc.1207491.
Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant DNA end-sensing and binding molecule. Inactivation of PARP-1 by chemicals and genetic mutations slows cell proliferation, increases sister chromatid exchange (SCE), micronuclei formation and chromosome instability, and shortens telomeres. Given its affinity to DNA breaks and temporal occupation on DNA strand break sites, PARP-1 is proposed to prevent inappropriate DNA recombination. We investigated the potential role of PARP-1 in repair of DNA double-strand breaks (DSBs) and stalled replication forks. PARP-1-/- embryonic stem cells and embryonic fibroblast cells exhibited normal repair of DNA DSBs by either homologous recombination (HR) or nonhomologous end-joining (NHEJ) pathways. Inactivation of PARP-1 did not interfere with gene-targeting efficiency in ES cells. However, PARP-1-/- cells were hypersensitive to the replication damage agent hydroxyurea (HU)-induced cell death and exhibited enhanced SCE formation. Ablation of PARP-1 delayed reactivation of stalled replication forks imposed by HU and re-entry into the G2-M phase after HU release. These data indicate that PARP-1 is dispensable in HR induced by DSBs, but is involved in the repair and reactivation of stalled replication forks.
聚（ADP - 核糖）聚合酶 -1（PARP -1）是一种丰富的DNA末端传感和结合分子。化学物质和基因突变导致的PARP -1失活会减缓细胞增殖，增加姐妹染色单体交换（SCE）、微核形成和染色体不稳定性，并缩短端粒。鉴于其对DNA断裂的亲和力以及在DNA链断裂位点的短暂占据，有人提出PARP -1可防止不适当的DNA重组。我们研究了PARP -1在DNA双链断裂（DSB）修复和停滞复制叉中的潜在作用。PARP -1基因敲除的胚胎干细胞和胚胎成纤维细胞通过同源重组（HR）或非同源末端连接（NHEJ）途径对DNA DSB表现出正常的修复能力。PARP -1失活并不影响ES细胞中的基因靶向效率。然而，PARP -1基因敲除的细胞对复制损伤剂羟基脲（HU）诱导的细胞死亡高度敏感，并表现出增强的SCE形成。PARP -1的缺失延迟了由HU导致的停滞复制叉的重新激活以及HU释放后重新进入G2 - M期。这些数据表明，PARP -1在DSB诱导的HR中是可有可无的，但参与了停滞复制叉的修复和重新激活。
