TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends

Cell. 2012 Aug 3;150(3):481-94. doi: 10.1016/j.cell.2012.07.012.

Abstract

Telomere synthesis in cancer cells and stem cells involves trafficking of telomerase to Cajal bodies, and telomerase is thought to be recruited to telomeres through interactions with telomere-binding proteins. Here, we show that the OB-fold domain of the telomere-binding protein TPP1 recruits telomerase to telomeres through an association with the telomerase reverse transcriptase TERT. When tethered away from telomeres and other telomere-binding proteins, the TPP1 OB-fold domain is sufficient to recruit telomerase to a heterologous chromatin locus. Expression of a minimal TPP1 OB-fold inhibits telomere maintenance by blocking access of telomerase to its cognate binding site at telomeres. We identify amino acids required for the TPP1-telomerase interaction, including specific loop residues within the TPP1 OB-fold domain and individual residues within TERT, some of which are mutated in a subset of pulmonary fibrosis patients. These data define a potential interface for telomerase-TPP1 interaction required for telomere maintenance and implicate defective telomerase recruitment in telomerase-related disease.

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

  • Amino Acid Sequence
  • Cell Line
  • Cell Line, Tumor
  • Coiled Bodies / metabolism
  • Humans
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Structure, Tertiary
  • Saccharomyces cerevisiae / metabolism
  • Sequence Alignment
  • Telomerase / chemistry
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Telomere / metabolism*
  • Telomere-Binding Proteins / chemistry*
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism*

Substances

  • ACD protein, human
  • Telomere-Binding Proteins
  • TERT protein, human
  • Telomerase