Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 30, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2024889118
Keywords
shelterin protein TPP1; separation-of-function; telomere extension; telomerase processivity; separation long-term cell
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Funding
- American Cancer Society [RSG-12-069-01-DMC]
- University of California Cancer Research Coordinating Committee
- University of California, Davis Faculty Bridge Funding
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The study found that mutations in the TEL region of human TPP1 impair telomerase processivity while leaving telomerase recruitment unaffected. This uncouples the two roles of TPP1 in regulating telomerase, demonstrating that TPP1 can regulate telomerase processivity separately from its role in recruiting telomerase.
The shelterin protein TPP1 is involved in both recruiting telomerase and stimulating telomerase processivity in human cells. Assessing the in vivo significance of the latter role of TPP1 has been difficult, because TPP1 mutations that perturb telomerase function tend to abolish both telomerase recruitment and processivity. The Saccharomyces cerevisiae telomerase-associated Est3 protein adopts a protein fold similar to the N-terminal region of TPP1. Interestingly, a previous structure-guided mutagenesis study of Est3 revealed a TELR surface region that regulates telomerase function via an unknown mechanism without affecting the interaction between Est3 and telomerase [T. Rao et al., Proc. Natl. Acad. Sci. U.S.A. 111, 214-218 (2014)]. Here, we show that mutations within the structurally conserved TELR region on human TPP1 impaired telomerase processivity while leaving telomerase recruitment unperturbed, hence uncoupling the two roles of TPP1 in regulating telomerase. Telomeres in cell lines containing homozygous TELR mutations progressively shortened to a critical length that caused cellular senescence, despite the presence of abundant telomerase in these cells. Our findings not only demonstrate that telomerase processivity can be regulated by TPP1 in a process separable from its role in recruiting telomerase, but also establish that the in vivo stimulation of telomerase processivity by TPP1 is critical for telomere length homeostasis and long-term viability of human cells.
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