title: Nemo-like kinase is critical for p53 stabilization and function in response to DNA damage.
abstract: The DNA damage response (DDR) acts as a protective mechanism for maintaining cell homeostasis. Nemo-like kinase (NLK) is a serine/threonine-protein kinase that has an important role in many pathways; however, its function in the DDR has not yet been defined. In our study, NLK-deficient HCT116 cells were found to be resistant to etoposide-induced cell death. We demonstrated that NLK is required for p53 activation in response to DNA damage. Remarkably, mechanistic studies revealed that NLK interacts with p53 and stabilizes p53 by blocking MDM2-mediated p53 ubiquitination and degradation. Furthermore, NLK enhances p53 activity and affects expression downstream of p53. Interestingly, these functions of NLK are not related to its kinase activity. Consistent with these results, NLK-deficient cells have a resistance effect on DNA damage. Therefore, these findings emphasize that NLK is a novel factor in DDR mechanisms.
authors.affiliation: Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: H-H
authors.initials: HH
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: S-Z
authors.initials: SZ
authors.lastname: Li
authors.affiliation: Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: X-M
authors.initials: XM
authors.lastname: Hu
authors.affiliation: Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: P-N
authors.initials: PN
authors.lastname: Hou
authors.affiliation: Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China.
authors.forename: L
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: R-L
authors.initials: RL
authors.lastname: Du
authors.affiliation: Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: X-D
authors.initials: XD
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047908:Intracellular Signaling Peptides and Proteins; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C470551:NLK protein, human; D017346:Protein Serine-Threonine Kinases