NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres

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

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.

MeSH terms

  • Aminopeptidases / genetics
  • Aminopeptidases / metabolism
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Binding Sites
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair*
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
  • Exodeoxyribonucleases
  • G1 Phase
  • G2 Phase
  • HCT116 Cells
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Models, Molecular
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • S Phase
  • Serine Proteases / genetics
  • Serine Proteases / metabolism
  • Structure-Activity Relationship
  • Telomere / genetics
  • Telomere / metabolism*
  • Telomere / pathology
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism
  • Telomeric Repeat Binding Protein 2 / chemistry
  • Telomeric Repeat Binding Protein 2 / genetics
  • Telomeric Repeat Binding Protein 2 / metabolism*

Substances

  • BIRC6 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Inhibitor of Apoptosis Proteins
  • NBN protein, human
  • Nijmegen breakage syndrome 1 protein, mouse
  • Nuclear Proteins
  • POT1 protein, human
  • TERF2 protein, human
  • TRF2 protein, mouse
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • DCLRE1B protein, human
  • Exodeoxyribonucleases
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • tripeptidyl-peptidase 1
  • DNA Repair Enzymes