title: ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells.
abstract: 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.
authors.affiliation: Department of Otorhinolaryngology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Ka
authors.initials: K
authors.lastname: Bian
authors.affiliation: Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA.
authors.forename: Naveen Reddy
authors.initials: NR
authors.lastname: Muppani
authors.affiliation: Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA.
authors.forename: Lobna
authors.initials: L
authors.lastname: Elkhadragy
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Tenghui
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Sungyun
authors.initials: S
authors.lastname: Jung
authors.affiliation: Department of Pharmacy, University of Tromsoe, N-Tromsoe, Norway.
authors.forename: Ole Morten
authors.initials: OM
authors.lastname: Seternes
authors.affiliation: Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA.|Department of Otorhinolaryngology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Long
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D048053:Mitogen-Activated Protein Kinase 6 / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D010766:Phosphorylation; D000075223:Poly-ADP-Ribose Binding Proteins; D011499:Protein Processing, Post-Translational; D061987:Sf9 Cells; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D005047:Etoposide; D048053:Mitogen-Activated Protein Kinase 6; D010727:Phosphoric Diester Hydrolases; C474866:TDP2 protein, human; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human
keywords: DNA damage; ERK3; TDP2; Top2 inhibitors; chemoresistance