title: A balance between elongation and trimming regulates telomere stability in stem cells.
abstract: Telomere length maintenance ensures self-renewal of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs); however, the mechanisms governing telomere length homeostasis in these cell types are unclear. Here, we report that telomere length is determined by the balance between telomere elongation, which is mediated by telomerase, and telomere trimming, which is controlled by XRCC3 and Nbs1, homologous recombination proteins that generate single-stranded C-rich telomeric DNA and double-stranded telomeric circular DNA (T-circles), respectively. We found that reprogramming of differentiated cells induces T-circle and single-stranded C-rich telomeric DNA accumulation, indicating the activation of telomere trimming pathways that compensate telomerase-dependent telomere elongation in hiPSCs. Excessive telomere elongation compromises telomere stability and promotes the formation of partially single-stranded telomeric DNA circles (C-circles) in hESCs, suggesting heightened sensitivity of stem cells to replication stress at overly long telomeres. Thus, tight control of telomere length homeostasis is essential to maintain telomere stability in hESCs.
authors.affiliation: Molecular and Cellular Biology Department, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rivera
authors.affiliation: Molecular and Cellular Biology Department, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Candy
authors.initials: C
authors.lastname: Haggblom
authors.affiliation: DiSTABiF, Second University of Naples, Caserta, Italy.
authors.forename: Sandro
authors.identifier: 0000-0002-8900-0968
authors.initials: S
authors.lastname: Cosconati
authors.affiliation: Molecular and Cellular Biology Department, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Karlseder
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; C110901:X-ray repair cross complementing protein 3