کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2035694 | 1072212 | 2012 | 14 صفحه PDF | دانلود رایگان |
SummaryTelomere 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.
Graphical AbstractFigure optionsDownload high-quality image (226 K)Download as PowerPoint slideHighlights
► Enforced expression of telomerase forms neo-Cajal bodies at telomeres
► TPP1 OB-fold domain recruits telomerase to a heterologous chromatin locus
► TPP1-OB alone sequesters telomerase within Cajal bodies and causes telomere shortening
► OB-fold mutations and some disease mutations in TERT block telomerase recruitment
Journal: - Volume 150, Issue 3, 3 August 2012, Pages 481–494