title: NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres.
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 NBS1429YQLSP433motif interacts specifically with the TRF2TRFHdomain. 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 NBS1S432to activate ATM, while interaction of de-phosphorylated NBS1S432with TRF2 promotes alternative-NHEJ repair of telomeres lacking POT1-TPP1. Our work advances understanding of how the TRF2TRFHdomain orchestrates telomere end protection and reveals how the phosphorylation status of the NBS1S432dictates repair pathway choice of dysfunctional telomeres.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Rai
authors.affiliation: 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.
authors.forename: Chunyi
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Cayla
authors.initials: C
authors.lastname: Broton
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: 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.
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism; D005090:Exodeoxyribonucleases; D016193:G1 Phase; D016195:G2 Phase; D045325:HCT116 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016196:S Phase; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex; D013329:Structure-Activity Relationship; D016615:Telomere / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C495876:ACD protein, human; C544060:Acd protein, mouse; C401541:BIRC6 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; C112156:NBN protein, human; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; C440849:POT1 protein, human; D000089804:Shelterin Complex; C504753:TERF2 protein, human; C534796:TRF2 protein, mouse; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C493741:DCLRE1B protein, human; D005090:Exodeoxyribonucleases; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D045643:DNA Repair Enzymes