TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs.
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.
Kim
Hyeung
H
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Lee
Ok-Hee
OH
Xin
Huawei
H
Chen
Liuh-Yow
LY
Qin
Jun
J
Chae
Heekyung Kate
HK
Lin
Shiaw-Yih
SY
Safari
Amin
A
Liu
Dan
D
Songyang
Zhou
Z
D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002460:Cell Line; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D016601:RNA-Binding Proteins / Q000378:metabolism; D016615:Telomere; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C110225:PPP1R10 protein, human; D016601:RNA-Binding Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2