title: Nek7 Protects Telomeres from Oxidative DNA Damage by Phosphorylation and Stabilization of TRF1.
abstract: Telomeric repeat binding factor 1 (TRF1) is essential to the maintenance of telomere chromatin structure and integrity. However, how telomere integrity is maintained, especially in response to damage, remains poorly understood. Here, we identify Nek7, a member of the Never in Mitosis Gene A (NIMA) kinase family, as a regulator of telomere integrity. Nek7 is recruited to telomeres and stabilizes TRF1 at telomeres after damage in an ATM activation-dependent manner. Nek7 deficiency leads to telomere aberrations, long-lasting γH2AX and 53BP1 foci, and augmented cell death upon oxidative telomeric DNA damage. Mechanistically, Nek7 interacts with and phosphorylates TRF1 on Ser114, which prevents TRF1 from binding to Fbx4, an Skp1-Cul1-F box E3 ligase subunit, thereby alleviating proteasomal degradation of TRF1, leading to a stable association of TRF1 with Tin2 to form a shelterin complex. Our data reveal a mechanism of efficient protection of telomeres from damage through Nek7-dependent stabilization of TRF1.
authors.affiliation: Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Tan
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Sun
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hellwig
authors.affiliation: Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, 3501 Fifth Avenue, 9th Floor Biomedical Science Tower III, Pittsburgh, PA 15261, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zeng
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA; Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, 3501 Fifth Avenue, 9th Floor Biomedical Science Tower III, Pittsburgh, PA 15261, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, 3500 Terrace Street, S362 Biomedical Science Tower S, Pittsburgh, PA 15261, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Yates
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Smithgall
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, W1058 Thomas E. Starzl Biomedical Science Tower, Pittsburgh, PA 15261, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Levine
authors.affiliation: Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Department of Immunobiology and the Vascular Biology and Therapeutics Program, Yale School of Medicine, 10 Amistad Street, PO Box 208011, New Haven, CT 06520, USA. Electronic address: bing.su@yale.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Su
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA. Electronic address: lil64@pitt.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Lan
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D004249:DNA Damage; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D000072379:NIMA-Related Kinases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D034622:RNA Interference; D000089804:Shelterin Complex; D016615:Telomere / Q000201:enzymology* / Q000235:genetics / Q000528:radiation effects; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C508146:FBXO4 protein, human; C468783:H2AX protein, human; D006657:Histones; D000089804:Shelterin Complex; C059329:TERF1 protein, human; C440868:TINF2 protein, human; C498301:TP53BP1 protein, human; D034501:Telomere-Binding Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C512685:NEK7 protein, human; D000072379:NIMA-Related Kinases; D046988:Proteasome Endopeptidase Complex
keywords: KillerRed; Nek7; TRF1; oxidative DNA damage; phosphorylation; telomere