Wang Shouyu, Gong Zhenghua, Chen Rui, Liu Yunru, Li Aiping, Li Gang, Zhou Jianwei
Department of Molecular Cell Biology and Toxicology, Cancer Centre, School of Public Health, Nanjing Medical University, Nanjing 210029, People's Republic of China.
Nucleic Acids Res. 2009 Apr;37(6):1936-50. doi: 10.1093/nar/gkp054. Epub 2009 Feb 10.
JWA was recently demonstrated to be involved in cellular responses to environmental stress including oxidative stress. Although it was found that JWA protected cells from reactive oxygen species-induced DNA damage, upregulated base excision repair (BER) protein XRCC1 and downregulated PARP-1, the molecular mechanism of JWA in regulating the repair of DNA single-strand breaks (SSBs) is still unclear. Our present studies demonstrated that a reduction in JWA protein levels in cells resulted in a decrease of SSB repair capacity and hypersensitivity to DNA-damaging agents such as methyl methanesulfonate and hydrogen peroxide. JWA functioned as a repair protein by multi-interaction with XRCC1. On the one hand, JWA was translocated into the nucleus by the carrier protein XRCC1 and co-localized with XRCC1 foci after oxidative DNA damage. On the other hand, JWA via MAPK signaling pathway regulated nuclear factor E2F1, which further transcriptionally regulated XRCC1. In addition, JWA protected XRCC1 protein from ubiquitination and degradation by proteasome. These findings indicate that JWA may serve as a novel regulator of XRCC1 in the BER protein complex to facilitate the repair of DNA SSBs.
最近研究表明，JWA参与细胞对包括氧化应激在内的环境应激的反应。尽管发现JWA可保护细胞免受活性氧诱导的DNA损伤，上调碱基切除修复（BER）蛋白XRCC1并下调PARP-1，但JWA调节DNA单链断裂（SSB）修复的分子机制仍不清楚。我们目前的研究表明，细胞中JWA蛋白水平的降低导致SSB修复能力下降以及对诸如甲磺酸甲酯和过氧化氢等DNA损伤剂的超敏反应。JWA通过与XRCC1的多重相互作用发挥修复蛋白的作用。一方面，JWA通过载体蛋白XRCC1转运至细胞核，并在氧化性DNA损伤后与XRCC1病灶共定位。另一方面，JWA通过丝裂原活化蛋白激酶（MAPK）信号通路调节核因子E2F1，进而对XRCC1进行转录调控。此外，JWA保护XRCC1蛋白不被蛋白酶体泛素化和降解。这些发现表明，JWA可能作为BER蛋白复合物中XRCC1的新型调节因子，促进DNA SSB的修复。
