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.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Wanil
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Ludlow
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Min
authors.affiliation: Faculté de Médecine, Tour Pasteur 8éme Étage, Nice, France.
authors.forename: Jerome D
authors.initials: JD
authors.lastname: Robin
authors.affiliation: Berkeley Lights, Inc., Emeryville, California, United States of America.
authors.forename: Guido
authors.initials: G
authors.lastname: Stadler
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Ilgen
authors.initials: I
authors.lastname: Mender
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Tsung-Po
authors.initials: TP
authors.lastname: Lai
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Woodring E
authors.initials: WE
authors.lastname: Wright
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D002895:Chromosomes, Human, Pair 5; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D011323:Primates / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D016615:Telomere
chemical_list: C509186:TERT protein, human; D019098:Telomerase