TPP1 OB-Fold Domain Controls Telomere Maintenance by Recruiting Telomerase to Chromosome Ends

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. [Display omitted] ► 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 The shelterin component TPP1 recruits telomerase from storage in Cajal bodies via a direct interaction with the enzyme’s catalytic subunit TERT. Mutations in TERT found associated with an idiopathic lung disease disrupt the interaction and impair telomerase mobilization.