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Mechanism of processive telomerase catalysis revealed by high-resolution optical tweezers

Eric M. Patrick, Joseph Slivka, Bramyn Payne, Matthew J. Comstock, View ORCID ProfileJens C. Schmidt
doi: https://doi.org/10.1101/700294
Eric M. Patrick
1Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI, U.S.A
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Joseph Slivka
2Department of Physics and Astronomy, Michigan State University, East Lansing MI, U.S.A
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Bramyn Payne
2Department of Physics and Astronomy, Michigan State University, East Lansing MI, U.S.A
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Matthew J. Comstock
2Department of Physics and Astronomy, Michigan State University, East Lansing MI, U.S.A
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  • For correspondence: schmi706@msu.edu mjcomsto@msu.edu
Jens C. Schmidt
1Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI, U.S.A
3Department of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, East Lansing MI, U.S.A
4Department of Biomedical Engineering, Michigan State University, East Lansing MI, U.S.A
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  • ORCID record for Jens C. Schmidt
  • For correspondence: schmi706@msu.edu mjcomsto@msu.edu
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Abstract

Telomere maintenance by telomerase is essential for continuous proliferation of human cells and is vital for the survival of stem cells and 90% of cancer cells. To compensate for telomeric DNA lost during DNA replication, telomerase processively adds GGTTAG repeats to chromosome ends by copying the template region within its RNA subunit. Between repeat additions, the RNA template must be recycled. How telomerase remains associated with substrate DNA during this critical translocation step remains unknown. Using a newly developed single-molecule telomerase activity assay utilizing high-resolution optical tweezers, we demonstrate that stable substrate DNA binding at an anchor site within telomerase facilitates the processive synthesis of telomeric repeats. After release of multiple telomeric repeats from telomerase, we observed folding of product DNA into G-quadruplex structures. Our results provide detailed mechanistic insights into telomerase catalysis, a process of critical importance in aging and cancer.

Footnotes

  • Text was updated to include extensive introduction and discussion. Figures were re-organized to include more data in the main figures. Improved analysis of G-Quadruplex formation was added (Fig. 5 and Supplementary Figure 4).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 23, 2019.
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Mechanism of processive telomerase catalysis revealed by high-resolution optical tweezers
Eric M. Patrick, Joseph Slivka, Bramyn Payne, Matthew J. Comstock, Jens C. Schmidt
bioRxiv 700294; doi: https://doi.org/10.1101/700294
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Mechanism of processive telomerase catalysis revealed by high-resolution optical tweezers
Eric M. Patrick, Joseph Slivka, Bramyn Payne, Matthew J. Comstock, Jens C. Schmidt
bioRxiv 700294; doi: https://doi.org/10.1101/700294

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