ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells
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Ka Bian2, Naveen Reddy Muppani1, Lobna Elkhadragy1, Wei Wang3, Cheng Zhang1, Tenghui Chen4, Sungyun Jung3, Ole Morten Seternes5 and Weiwen Long1,2
1 Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
2 Department of Otorhinolaryngology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China
3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
4 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5 Department of Pharmacy, University of Tromsoe, N-Tromsoe, Norway
Weiwen Long, email:
Keywords: ERK3, TDP2, Top2 inhibitors, DNA damage, chemoresistance
Received: June 01, 2015 Accepted: December 12, 2015 Published: December 19, 2015
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.
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