Wang Minli, Wu Weizhong, Wu Wenqi, Rosidi Bustanur, Zhang Lihua, Wang Huichen, Iliakis George
University of Duisburg-Essen, Medical School, Institute of Medical Radiation Biology, Hufeland street 55, 45122 Essen, Germany.
Nucleic Acids Res. 2006;34(21):6170-82. doi: 10.1093/nar/gkl840. Epub 2006 Nov 6.
Poly(ADP-ribose)polymerase 1 (PARP-1) recognizes DNA strand interruptions in vivo and triggers its own modification as well as that of other proteins by the sequential addition of ADP-ribose to form polymers. This modification causes a release of PARP-1 from DNA ends and initiates a variety of responses including DNA repair. While PARP-1 has been firmly implicated in base excision and single strand break repair, its role in the repair of DNA double strand breaks (DSBs) remains unclear. Here, we show that PARP-1, probably together with DNA ligase III, operates in an alternative pathway of non-homologous end joining (NHEJ) that functions as backup to the classical pathway of NHEJ that utilizes DNA-PKcs, Ku, DNA ligase IV, XRCC4, XLF/Cernunnos and Artemis. PARP-1 binds to DNA ends in direct competition with Ku. However, in irradiated cells the higher affinity of Ku for DSBs and an excessive number of other forms of competing DNA lesions limit its contribution to DSB repair. When essential components of the classical pathway of NHEJ are absent, PARP-1 is recruited for DSB repair, particularly in the absence of Ku and non-DSB lesions. This form of DSB repair is sensitive to PARP-1 inhibitors. The results define the function of PARP-1 in DSB repair and characterize a candidate pathway responsible for joining errors causing genomic instability and cancer.
聚（ADP-核糖）聚合酶1（PARP-1）在体内识别DNA链断裂，并通过依次添加ADP-核糖形成聚合物来触发自身以及其他蛋白质的修饰。这种修饰导致PARP-1从DNA末端释放，并引发包括DNA修复在内的多种反应。虽然PARP-1已被明确与碱基切除和单链断裂修复有关，但其在DNA双链断裂（DSB）修复中的作用仍不清楚。在此，我们表明PARP-1可能与DNA连接酶III一起，在非同源末端连接（NHEJ）的替代途径中发挥作用，该途径作为利用DNA-PKcs、Ku、DNA连接酶IV、XRCC4、XLF/Cernunnos和Artemis的经典NHEJ途径的备份。PARP-1与Ku直接竞争结合到DNA末端。然而，在受辐照的细胞中，Ku对DSB的更高亲和力以及大量其他形式的竞争性DNA损伤限制了其对DSB修复的贡献。当经典NHEJ途径的关键成分缺失时，PARP-1被招募用于DSB修复，特别是在没有Ku和非DSB损伤的情况下。这种形式的DSB修复对PARP-1抑制剂敏感。这些结果定义了PARP-1在DSB修复中的功能，并表征了一个导致连接错误从而引起基因组不稳定和癌症的候选途径。
