Bian Ka, Muppani Naveen Reddy, Elkhadragy Lobna, Wang Wei, Zhang Cheng, Chen Tenghui, Jung Sungyun, Seternes Ole Morten, Long Weiwen
Department of Otorhinolaryngology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA.
Oncotarget. 2016 Feb 9;7(6):6665-75. doi: 10.18632/oncotarget.6682.
Posttranslational modifications (PTMs), such as phosphorylation and ubiquitination, play critical regulatory roles in the assembly of DNA damage response proteins on the DNA damage site and their activities in DNA damage repair. Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-linked DNA damage, thereby protecting cancer cells against Top2 inhibitors-induced growth inhibition and cell death. The regulation of TDP2 activity by post-translational modifications in DNA repair, however, remains unclear. In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition. As such, our study revealed a post-translational regulation of TDP2 activity and discovered a new role of ERK3 in increasing cancer cells' DNA damage response and chemoresistance to Top2 inhibitors.
翻译后修饰（PTMs），如磷酸化和泛素化，在DNA损伤反应蛋白在DNA损伤位点的组装及其在DNA损伤修复中的活性方面发挥着关键的调节作用。酪氨酰DNA磷酸二酯酶2（TDP2）修复拓扑异构酶2（Top2）相关的DNA损伤，从而保护癌细胞免受Top2抑制剂诱导的生长抑制和细胞死亡。然而，DNA修复中翻译后修饰对TDP2活性的调节仍不清楚。在本研究中，我们发现非典型丝裂原活化蛋白激酶ERK3在S60位点磷酸化TDP2并调节TDP2的磷酸二酯酶活性，从而协同保护肺癌细胞免受Top2抑制剂诱导的DNA损伤和生长抑制。因此，我们的研究揭示了TDP2活性的翻译后调控，并发现了ERK3在增强癌细胞DNA损伤反应和对Top2抑制剂的化疗耐药性方面的新作用。
