Nek7 Protects Telomeres from Oxidative DNA Damage by Phosphorylation and Stabilization of TRF1

Rong Tan; Satoshi Nakajima; Qun Wang; Hongxiang Sun; Jing Xue; Jian Wu; Sabine Hellwig; Xuemei Zeng; Nathan A Yates; Thomas E Smithgall; Ming Lei; Yu Jiang; Arthur S Levine; Bing Su; Li Lan

doi:10.1016/j.molcel.2017.01.015

Nek7 Protects Telomeres from Oxidative DNA Damage by Phosphorylation and Stabilization of TRF1

Mol Cell. 2017 Mar 2;65(5):818-831.e5. doi: 10.1016/j.molcel.2017.01.015. Epub 2017 Feb 16.

Authors

Rong Tan¹, Satoshi Nakajima², Qun Wang³, Hongxiang Sun³, Jing Xue⁴, Jian Wu⁴, Sabine Hellwig⁵, Xuemei Zeng⁶, Nathan A Yates⁷, Thomas E Smithgall⁵, Ming Lei⁴, Yu Jiang⁸, Arthur S Levine², Bing Su⁹, Li Lan¹⁰

Affiliations

¹ 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.
² 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.
³ Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
⁴ Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
⁵ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA.
⁶ 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.
⁷ 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.
⁸ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, W1058 Thomas E. Starzl Biomedical Science Tower, Pittsburgh, PA 15261, USA.
⁹ 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: [email protected].
¹⁰ 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: [email protected].

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.

Keywords: KillerRed; Nek7; TRF1; oxidative DNA damage; phosphorylation; telomere.

MeSH terms

Ataxia Telangiectasia Mutated Proteins / genetics
Ataxia Telangiectasia Mutated Proteins / metabolism
Binding Sites
DNA Damage*
F-Box Proteins / genetics
F-Box Proteins / metabolism
HEK293 Cells
HeLa Cells
Histones / metabolism
Humans
NIMA-Related Kinases / genetics
NIMA-Related Kinases / metabolism*
Oxidative Stress*
Phosphorylation
Proteasome Endopeptidase Complex / metabolism
Protein Binding
Protein Stability
RNA Interference
Shelterin Complex
Telomere / enzymology*
Telomere / genetics
Telomere / radiation effects
Telomere-Binding Proteins / genetics
Telomere-Binding Proteins / metabolism*
Time Factors
Transfection
Tumor Suppressor p53-Binding Protein 1 / genetics
Tumor Suppressor p53-Binding Protein 1 / metabolism
Ubiquitination

Substances

F-Box Proteins
FBXO4 protein, human
H2AX protein, human
Histones
Shelterin Complex
TERF1 protein, human
TINF2 protein, human
TP53BP1 protein, human
Telomere-Binding Proteins
Tumor Suppressor p53-Binding Protein 1
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
NEK7 protein, human
NIMA-Related Kinases
Proteasome Endopeptidase Complex

Abstract

MeSH terms

Substances

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