Telomere length is tightly regulated in cells that express telomerase. The Saccharomyces cerevisiae Ku heterodimer, a DNA end-binding complex, positively regulates telomere length in a telomerase-dependent manner. Ku associates with the telomerase RNA subunit TLC1, and this association is required for TLC1 nuclear retention. Ku-TLC1 interaction also impacts the cell-cycle-regulated association of the telomerase catalytic subunit Est2 to telomeres. The promotion of TLC1 nuclear localization and Est2 recruitment have been proposed to be the principal role of Ku in telomere length maintenance, but neither model has been directly tested. Here we study the impact of forced recruitment of Est2 to telomeres on telomere length in the absence of Ku's ability to bind TLC1 or DNA ends. We show that tethering Est2 to telomeres does not promote efficient telomere elongation in the absence of Ku-TLC1 interaction or DNA end binding. Moreover, restoration of TLC1 nuclear localization, even when combined with Est2 recruitment, does not bypass the role of Ku. In contrast, forced recruitment of Est1, which has roles in telomerase recruitment and activation, to telomeres promotes efficient and progressive telomere elongation in the absence of Ku-TLC1 interaction, Ku DNA end binding, or Ku altogether. Ku associates with Est1 and Est2 in a TLC1-dependent manner and enhances Est1 recruitment to telomeres independently of Est2. Together, our results unexpectedly demonstrate that the principal role of Ku in telomere length maintenance is to promote the association of Est1 with telomeres, which may in turn allow for efficient recruitment and activation of the telomerase holoenzyme.
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http://dx.doi.org/10.1534/genetics.114.164707 | DOI Listing |
Nat Cell Biol
January 2025
Genome Integrity Unit, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
Double-strand breaks (DSBs) can initiate mitotic catastrophe, a complex oncosuppressive phenomenon characterized by cell death during or after cell division. Here we unveil how cell cycle-regulated DSB repair guides disparate cell death outcomes through single-cell analysis of extended live imaging. Following DSB induction in S or G2, passage of unresolved homologous recombination intermediates into mitosis promotes non-immunogenic intrinsic apoptosis in the immediate attempt at cell division.
View Article and Find Full Text PDFJ Clin Periodontol
January 2025
Department of Biomedical Sciences, School of Dental Medicine, University of Nevada, Las Vegas, Las Vegas, Nevada, USA.
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View Article and Find Full Text PDFMech Ageing Dev
January 2025
Department of Medicine, Academy of Applied Medical and Social Sciences-AMiSNS: Akademia Medycznych I Spolecznych Nauk Stosowanych-2 Lotnicza Street, 82-300 Elbląg, Poland; Department of General Surgery and Surgical Oncology, "Saint Wojciech" Hospital, "Nicolaus Copernicus" Health Center, Jana Pawła II 50, 80-462 Gdańsk, Poland.
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View Article and Find Full Text PDFModification and deterioration of old-growth forests by industrial forestry have seriously threatened species diversity worldwide. The loss of natural habitats increases the concentration of circulating glucocorticoids and incurs chronic stress in animals, influencing the immune system, growth, survival, and lifespan of animals inhabiting such areas. In this study, we tested whether great tit () nestlings grown in old-growth unmanaged coniferous forests have longer telomeres than great tit nestlings developing in young managed coniferous forests.
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