Open Access
Proceedings of the National Academy of Sciences of the United States of America, volume 111, issue 31, pages 11311-11316
A self-regulating template in human telomerase
Brown Andrew F.
1
,
Podlevsky Joshua D
1
,
Qi Xiaodong
1
,
Chen Yinnan
1
,
Xie Mingyi
1
,
Chen Julian J L
1
1
Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287
|
Publication type: Journal Article
Publication date: 2014-06-30
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 11.1
ISSN: 00278424, 10916490
PubMed ID:
24982163
Multidisciplinary
Abstract
Significance The telomerase enzyme is essential for maintaining the replicative capacity of highly prolific cells, such as stem cells and cancer, by synthesizing telomeric DNA onto chromosome ends. Telomerase functions as an RNA–protein complex with an integral telomerase RNA (TR) component. While the templates from all other reverse transcriptases (RTs) merely specify the sequence for nucleotide addition, we found that the human TR template is embedded with a single-residue pausing signal for regulating DNA synthesis. Mutation of this pausing signal alters the fundamental function of telomerase for synthesizing exact telomeric DNA repeats. This is the first instance, to our knowledge, of a single-residue pausing signal found in the RNA template of an RT. Telomerase is a specialized reverse transcriptase (RT) containing an intrinsic telomerase RNA (TR) component. It synthesizes telomeric DNA repeats, (GGTTAG)n in humans, by reiteratively copying a precisely defined, short template sequence from the integral TR. The specific mechanism of how the telomerase active site uses this short template region accurately and efficiently during processive DNA repeat synthesis has remained elusive. Here we report that the human TR template, in addition to specifying the DNA sequence, is embedded with a single-nucleotide signal to pause DNA synthesis. After the addition of a dT residue to the DNA primer, which is specified by the 49 rA residue in the template, telomerase extends the DNA primer with three additional nucleotides and then pauses DNA synthesis. This sequence-defined pause site coincides precisely with the helix paired region 1 (P1)-defined physical template boundary and precludes the incorporation of nontelomeric nucleotides from residues outside the template region. Furthermore, this sequence-defined pausing mechanism is a key determinant, in addition to the P1-defined template boundary, for generating the characteristic 6-nt ladder banding pattern of telomeric DNA products in vitro. In the absence of the pausing signal, telomerase stalls nucleotide addition at multiple sites along the template, generating DNA products with heterogeneous terminal repeat registers. Our findings demonstrate that this unique self-regulating mechanism of the human TR template is essential for high-fidelity synthesis of DNA repeats.
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Brown A. F. et al. A self-regulating template in human telomerase // Proceedings of the National Academy of Sciences of the United States of America. 2014. Vol. 111. No. 31. pp. 11311-11316.
GOST all authors (up to 50)
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Brown A. F., Podlevsky J. D., Qi X., Chen Y., Xie M., Chen J. J. L. A self-regulating template in human telomerase // Proceedings of the National Academy of Sciences of the United States of America. 2014. Vol. 111. No. 31. pp. 11311-11316.
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TY - JOUR
DO - 10.1073/pnas.1402531111
UR - https://doi.org/10.1073%2Fpnas.1402531111
TI - A self-regulating template in human telomerase
T2 - Proceedings of the National Academy of Sciences of the United States of America
AU - Brown, Andrew F.
AU - Podlevsky, Joshua D
AU - Qi, Xiaodong
AU - Chen, Yinnan
AU - Xie, Mingyi
AU - Chen, Julian J L
PY - 2014
DA - 2014/06/30 00:00:00
PB - Proceedings of the National Academy of Sciences (PNAS)
SP - 11311-11316
IS - 31
VL - 111
PMID - 24982163
SN - 0027-8424
SN - 1091-6490
ER -
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@article{2014_Brown,
author = {Andrew F. Brown and Joshua D Podlevsky and Xiaodong Qi and Yinnan Chen and Mingyi Xie and Julian J L Chen},
title = {A self-regulating template in human telomerase},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2014},
volume = {111},
publisher = {Proceedings of the National Academy of Sciences (PNAS)},
month = {jun},
url = {https://doi.org/10.1073%2Fpnas.1402531111},
number = {31},
pages = {11311--11316},
doi = {10.1073/pnas.1402531111}
}
Cite this
MLA
Copy
Brown, Andrew F., et al. “A self-regulating template in human telomerase.” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 31, Jun. 2014, pp. 11311-11316. https://doi.org/10.1073%2Fpnas.1402531111.