@article{d5ae253ec824403ea2a0d92a44aba55c,
title = "Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer",
abstract = "Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal.",
author = "Wanil Kim and Ludlow, {Andrew T.} and Jaewon Min and Robin, {Jerome D.} and Guido Stadler and Ilgen Mender and Lai, {Tsung Po} and Ning Zhang and Wright, {Woodring E.} and Shay, {Jerry W.}",
note = "Funding Information: This work was performed in laboratories constructed with support from NIH grant C06 RR30414. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NCI (grant number CA124334-07).ATL was supported by an NCI T32. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Harold Simmons NCI Designated Comprehensive Cancer Center Support Grant (grant number CA142543).Grant to JWS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Institute on Aging (grant number AG01228).R01 to WEW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Southland Financial Corporation Distinguished Chain in Geriatic Research (grant number ).JWS and WEW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NCI (grant number KCA197672A).ATL was funded by a K99/R00 Pathway to Independence award. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NCI (grant number Lung SPORE P50CA70907).Funding to JWS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank for S.B. Kim, L. Zhang, and J. Peters-Hall for plasmids and cell lines; B. Holohan, and K. Batten for critical discussions; C. Cornelius, S. Barron, and M. Coquelin for technical assistance; the Live Cell Imaging Facility at UT Southwestern Medical Center for imaging analyses; the McDermott DNA sequencing core at UT Southwestern Medical Center. We thank Dr. Jay Schneider and Dr. Sean Goetsch for the kind gift of RNA from human stem cells. Publisher Copyright: {\textcopyright} 2016 Kim et al.",
year = "2016",
month = dec,
day = "15",
doi = "10.1371/journal.pbio.2000016",
language = "English (US)",
volume = "14",
journal = "PLoS Biology",
issn = "1544-9173",
publisher = "Public Library of Science",
number = "12",
}