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

Franklin L. Zhong, Luis F.Z. Batista, Adam Freund, Matthew F. Pech, Andrew S. Venteicher, Steven E. Artandi

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)481-494
Number of pages14
JournalCell
Volume150
Issue number3
DOIs
StatePublished - Aug 3 2012
Externally publishedYes

Bibliographical note

Funding Information:
We thank Amy Li for technical assistance and members of the Artandi lab for helpful discussion. F.L.Z. was supported by a fellowship from the Agency for Science, Technology, and Research (A ∗ STAR), Singapore. L.F.Z.B. was supported by a fellowship from the California Institute of Regenerative Medicine. A.F. was supported by NIH 5T32 CA09302. M.F.P. is the recipient of an NSF graduate research fellowship. This work was supported by NIH grants AG033747, CA125453, and CA111691, by a SCOR grant from the Leukemia and Lymphoma Society, and by the Glenn Foundation for Medical Research.

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