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Mol Cell. 2017 Mar 2;65(5):801-817.e4. doi: 10.1016/j.molcel.2017.01.016. Epub 2017 Feb 16.

NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres.

Author information

1
Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA.
2
National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA.
3
National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA; Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA.
4
National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA; Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA. Electronic address: leim@sibcb.ac.cn.
5
Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA; Molecular Biophysics and Biochemistry, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA. Electronic address: s.chang@yale.edu.

Abstract

Telomeres employ TRF2 to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), thereby repressing ATM-dependent DNA damage checkpoint responses. How TRF2 prevents MRN activation at dysfunctional telomeres is unclear. Here, we show that the phosphorylation status of NBS1 determines the repair pathway choice of dysfunctional telomeres. The crystal structure of the TRF2-NBS1 complex at 3.0 Å resolution shows that the NBS1 429YQLSP433 motif interacts specifically with the TRF2TRFH domain. Phosphorylation of NBS1 serine 432 by CDK2 in S/G2 dissociates NBS1 from TRF2, promoting TRF2-Apollo/SNM1B complex formation and the protection of leading-strand telomeres. Classical-NHEJ-mediated repair of telomeres lacking TRF2 requires phosphorylated NBS1S432 to activate ATM, while interaction of de-phosphorylated NBS1S432 with TRF2 promotes alternative-NHEJ repair of telomeres lacking POT1-TPP1. Our work advances understanding of how the TRF2TRFH domain orchestrates telomere end protection and reveals how the phosphorylation status of the NBS1S432 dictates repair pathway choice of dysfunctional telomeres.

PMID:
28216226
PMCID:
PMC5639704
DOI:
10.1016/j.molcel.2017.01.016
[Indexed for MEDLINE]
Free PMC Article

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