Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer

Wanil Kim, Andrew T. Ludlow, Jaewon Min, Jerome D. Robin, Guido Stadler, Ilgen Mender, Tsung Po Lai, Ning Zhang, Woodring E. Wright, Jerry W. Shay

Research output: Contribution to journalArticle

63 Scopus citations

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.

Original languageEnglish (US)
Article numbere2000016
JournalPLoS biology
Volume14
Issue number12
DOIs
StatePublished - Dec 15 2016

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Kim, W., Ludlow, A. T., Min, J., Robin, J. D., Stadler, G., Mender, I., Lai, T. P., Zhang, N., Wright, W. E., & Shay, J. W. (2016). Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer. PLoS biology, 14(12), [e2000016]. https://doi.org/10.1371/journal.pbio.2000016