期刊
MOLECULAR CELL
卷 65, 期 5, 页码 818-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2017.01.015
关键词
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资金
- NIH [GM118833, AG045545]
- National Natural Science Foundation of China [31470845, 81430033]
- Shanghai Science and Technology Commission [13JC1404700]
- UPCI Imaging Facility and UPCI Cytometry Facility
- National Institutes of Health [GM118833, P30 CA047904]
- UPCI Cancer Proteomics Facility/Biomedical Mass Spectrometry Center [P30CA047904]
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 gamma H2AX 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.
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