Neotelomere Formation by Telomerase in Human Cells
type: CreativeWork
description: Telomeres define and protect the ends of linear chromosomes. Genome stability requires that cells differentiate telomeres from DNA double-strand breaks (DSBs), which humans accomplish with the shelterin complex. The reverse transcriptase telomerase counteracts the shortening of telomeres that occurs with cell division due to incomplete DNA replication and nucleolytic resection. During human development, the expression of the reverse transcriptase component of telomerase (TERT) is restricted to the germ line and select stem cell pools, causing telomeres to shorten in most somatic cells. After a certain number of divisions, one or a few telomeres become too short to adequately suppress DNA damage response signaling, driving cells into senescence or apoptosis. Cells deficient in the p53 and Rb pathways, however, disregard these alarms, continue to divide, and ultimately enter telomere crisis, marked by restricted cell viability due to severe genome instability. During crisis, dysfunctional telomeres undergo repeated breakage-fusion-bridge cycles, forming dicentric chromosomes that snap during mitosis. Ultimately, clinically detectable tumors emerge from this process with shuffled, aneuploid genomes after acquiring a telomere maintenance mechanism, usually by reactivating TERT expression. Canonically, telomerase is believed to function in cancer by rapidly restoring critically short telomeres to a tolerable length and then maintaining replicative immortality thereafter. Nevertheless, this dogma does not explain how cells restore end protection to deeply damaged chromosomes, which likely require a mechanism for reestablishing their telomeres. We suspected that telomerase might aid incipient tumor cells in their escape from telomere crisis by healing broken chromosomes with neotelomeres. In a subset of human patients with terminal chromosome deletions, telomeric repeats directly abut reference genomic sequence at the breakpoint, suggesting that telomerase itself might hav…
abstract: Telomeres define and protect the ends of linear chromosomes. Genome stability requires that cells differentiate telomeres from DNA double-strand breaks (DSBs), which humans accomplish with the shelterin complex. The reverse transcriptase telomerase counteracts the shortening of telomeres that occurs with cell division due to incomplete DNA replication and nucleolytic resection. During human development, the expression of the reverse transcriptase component of telomerase (TERT) is restricted to the germ line and select stem cell pools, causing telomeres to shorten in most somatic cells. After a certain number of divisions, one or a few telomeres become too short to adequately suppress DNA damage response signaling, driving cells into senescence or apoptosis. Cells deficient in the p53 and Rb pathways, however, disregard these alarms, continue to divide, and ultimately enter telomere crisis, marked by restricted cell viability due to severe genome instability. During crisis, dysfunctional telomeres undergo repeated breakage-fusion-bridge cycles, forming dicentric chromosomes that snap during mitosis. Ultimately, clinically detectable tumors emerge from this process with shuffled, aneuploid genomes after acquiring a telomere maintenance mechanism, usually by reactivating TERT expression. Canonically, telomerase is believed to function in cancer by rapidly restoring critically short telomeres to a tolerable length and then maintaining replicative immortality thereafter. Nevertheless, this dogma does not explain how cells restore end protection to deeply damaged chromosomes, which likely require a mechanism for reestablishing their telomeres. We suspected that telomerase might aid incipient tumor cells in their escape from telomere crisis by healing broken chromosomes with neotelomeres. In a subset of human patients with terminal chromosome deletions, telomeric repeats directly abut reference genomic sequence at the breakpoint, suggesting that telomerase itself might hav…
author: Kinzig, Charles Gunnar
keywords: telomeres, telomerase, DNA double-strand breaks, neotelomeres, cancer, genome instability, Life Sciences
date published: 2023-01-01T08:00:00Z
date modified: 2026-07-24T04:10:47Z
provider: Rockefeller
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Rockefeller