Poly(ADP-ribose) polymerase 1 escorts XPC to UV-induced DNA lesions during nucleotide excision repair
Poly(ADP-ribose) polymerase 1 escorts XPC to UV-induced DNA lesions during nucleotide excision repair
复制标题
DOI：
10.1073/pnas.1706981114
复制
发表时间：
2017-08-15
影响因子：
11.1
通讯作者：
Shah, Girish M.
中科院分区：
文献类型：
--
作者：
Robu, Mihaela;Shah, Rashmi G.;Shah, Girish M.
着色性干皮病C（XPC）蛋白启动核苷酸切除修复（GG-NER）的全局基因组亚途径，以从基因组DNA去除UV诱导的直接光损伤。XPC具有识别和稳定DNA损伤位点的固有能力，并且这种功能在基因组背景下由UV损伤的DNA结合蛋白2（DDB 2）促进，DDB 2是多蛋白UV-DDB泛素连接酶复合物的一部分。核酶聚（ADP-核糖）聚合酶1（PARP 1）已被证明通过其与损伤位点处的DDB 2的相互作用促进GG-NER的损伤识别步骤。在这里，我们表明，PARP 1在招募和稳定XPC在紫外线诱导的DNA损伤，以促进GG-NER额外的DDB 2独立的直接作用。在照射前的稳态条件下，它与XPC在核质中形成稳定的复合物，并在UV照射后以DDB 2-独立的方式将其快速护送到受损的DNA。PARP 1的催化活性对于在核质中与XPC的初始复合物的形成不是必需的，但它增强了XPC在照射后向DNA损伤位点的募集。使用纯化的蛋白质，我们还表明，PARP 1-XPC复合物有利于在UV-DDB连接酶复合物的存在下，XPC的紫外线损伤部位的移交。因此，XPC在基因组环境中的病变搜索功能由XPC本身、DDB 2和PARP 1控制。我们的研究结果揭示了一种范式，即许多蛋白质在稳态条件下与PARP 1的已知相互作用可能对这些蛋白质具有功能意义。
Xeroderma pigmentosum C (XPC) protein initiates the global genomic subpathway of nucleotide excision repair (GG-NER) for removal of UV-induced direct photolesions from genomic DNA. The XPC has an inherent capacity to identify and stabilize at the DNA lesion sites, and this function is facilitated in the genomic context by UV-damaged DNA-binding protein 2 (DDB2), which is part of amultiprotein UV-DDB ubiquitin ligase complex. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) has been shown to facilitate the lesion recognition step of GG-NER via its interaction with DDB2 at the lesion site. Here, we show that PARP1 plays an additional DDB2-independent direct role in recruitment and stabilization of XPC at the UV-induced DNA lesions to promote GG-NER. It forms a stable complex with XPC in the nucleoplasm under steady-state conditions before irradiation and rapidly escorts it to the damaged DNA after UV irradiation in a DDB2-independent manner. The catalytic activity of PARP1 is not required for the initial complex formation with XPC in the nucleoplasm but it enhances the recruitment of XPC to the DNA lesion site after irradiation. Using purified proteins, we also show that the PARP1-XPC complex facilitates the handover of XPC to the UVlesion site in the presence of the UV-DDB ligase complex. Thus, the lesion search function of XPC in the genomic context is controlled by XPC itself, DDB2, and PARP1. Our results reveal a paradigm that the known interaction of many proteins with PARP1 under steady-state conditions could have functional significance for these proteins.