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.

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
  • 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
  • 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