TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs

Nat Struct Mol Biol. 2009 Apr;16(4):372-9. doi: 10.1038/nsmb.1575. Epub 2009 Mar 15.


In mammalian cells, the telomeric repeat binding factor (TRF) homology (TRFH) domain-containing telomeric proteins TRF1 and TRF2 associate with a collection of molecules necessary for telomere maintenance and cell-cycle progression. However, the specificity and the mechanisms by which TRF2 communicates with different signaling pathways remain largely unknown. Using oriented peptide libraries, we demonstrate that the TRFH domain of human TRF2 recognizes [Y/F]XL peptides with the consensus motif YYHKYRLSPL. Disrupting the interactions between the TRF2 TRFH domain and its targets resulted in telomeric DNA-damage responses. Furthermore, our genome-wide target analysis revealed phosphatase nuclear targeting subunit (PNUTS) and microcephalin 1 (MCPH1) as previously unreported telomere-associated proteins that directly interact with TRF2 via the [Y/F]XL motif. PNUTS and MCPH1 can regulate telomere length and the telomeric DNA-damage response, respectively. Our findings indicate that an array of TRF2 molecules functions as a protein hub and regulates telomeres by recruiting different signaling molecules via a linear sequence code.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Cycle Proteins
  • Cell Cycle*
  • Cell Line
  • Cytoskeletal Proteins
  • DNA-Binding Proteins / metabolism
  • Humans
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs*
  • Protein Interaction Mapping*
  • RNA-Binding Proteins / metabolism
  • Telomere*
  • Telomeric Repeat Binding Protein 2 / genetics
  • Telomeric Repeat Binding Protein 2 / metabolism*


  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • MCPH1 protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • PPP1R10 protein, human
  • RNA-Binding Proteins
  • TERF2 protein, human
  • Telomeric Repeat Binding Protein 2