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TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase

Nature volume 445, pages 559–562 (2007)Cite this article

Abstract

Telomere dysfunction may result in chromosomal abnormalities, DNA damage responses, and even cancer1. Early studies in lower organisms have helped to establish the crucial role of telomerase and telomeric proteins in maintaining telomere length and protecting telomere ends2,3,4,5,6,7. In Oxytricha nova, telomere G-overhangs are protected by the TEBP-α/β heterodimer3,4. Human telomeres contain duplex telomeric repeats with 3′ single-stranded G-overhangs, and may fold into a t-loop structure that helps to shield them from being recognized as DNA breaks8,9. Additionally, the TEBP-α homologue, POT1, which binds telomeric single-stranded DNA (ssDNA)10, associates with multiple telomeric proteins (for example, TPP1, TIN2, TRF1, TRF2 and RAP1) to form the six-protein telosome/shelterin11,12 and other subcomplexes. These telomeric protein complexes in turn interact with diverse pathways to form the telomere interactome13 for telomere maintenance. However, the mechanisms by which the POT1-containing telosome communicates with telomerase to regulate telomeres remain to be elucidated. Here we demonstrate that TPP1 is a putative mammalian homologue of TEBP-β and contains a predicted amino-terminal oligonucleotide/oligosaccharide binding (OB) fold. TPP1–POT1 association enhanced POT1 affinity for telomeric ssDNA. In addition, the TPP1 OB fold, as well as POT1–TPP1 binding, seemed critical for POT1-mediated telomere-length control and telomere-end protection in human cells. Disruption of POT1–TPP1 interaction by dominant negative TPP1 expression or RNA interference (RNAi) resulted in telomere-length alteration and DNA damage responses. Furthermore, we offer evidence that TPP1 associates with the telomerase in a TPP1-OB-fold-dependent manner, providing a physical link between telomerase and the telosome/shelterin complex. Our findings highlight the critical role of TPP1 in telomere maintenance, and support a yin–yang model in which TPP1 and POT1 function as a unit to protect human telomeres, by both positively and negatively regulating telomerase access to telomere DNA.

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Figure 1: TPP1 is a homologue of ciliate TEBP-β that interacts with POT1 to bind ssDNA.
Figure 2: POT1 telomeric targeting depends on POT1–TPP1 interaction.
Figure 3: The TPP1 OB fold and TPP1–POT1 interaction are important for telomere-end protection and -length control.
Figure 4: The TPP1 OB fold is important for recruitment of telomerase activity.

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Acknowledgements

We thank J. L. Chen for kindly providing the HA–TERT and hTR plasmids and we thank A. Laegeler, K. Huang and L.-Y. Chen for help. This work was supported by awards to Z.S. and D.L. from NIH, the Department of Defense, the American Cancer Society, and the American Heart Association. Z.S. is a Leukaemia and Lymphoma Society Scholar.

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  1. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Huawei Xin, Dan Liu, Ma Wan, Amin Safari, Hyeung Kim, Wen Sun, Matthew S. O’Connor & Zhou Songyang

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Correspondence to Zhou Songyang.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-S5 with legends supporting the model that TPP1 is a TEBP-β homologue that interacts and regulates POT1, Supplementary Methods with more detailed description of the methodologies and reagents used in the paper and Supplementary Notes which contain references cited in Supplementary Methods (PDF 1467 kb)

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Xin, H., Liu, D., Wan, M. et al. TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase. Nature 445, 559–562 (2007). https://doi.org/10.1038/nature05469

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