telomere association
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2021 ◽  
Author(s):  
Maria Sol Jacome Burbano ◽  
Jerome Robin ◽  
Serge Bauwens ◽  
Marjorie Martin ◽  
Emma Donati ◽  
...  

Longevity is determined by diverse signaling pathways including telomere protection and homeostasis master regulators like FOXO3a. We previously showed that the telomeric repeat binding factor 2 (TRF2) expression decreases with age in human skeletal muscle and that, surprisingly, its loss in myofibers does not trigger telomere deprotection. We reveal here that in TERF2-compromised myotubes, FOXO3a is recruited to telomeres where it acts as a protective factor against ATM-dependent DNA damage activation. Moreover, we show that FOXO3a-telomere association increases with age in human skeletal muscle biopsies. In mitotic fibroblasts, the telomere protective properties of FOXO3a are operative if the cells are treated with bleomycin. The telomere function of FOXO3a does not require its Forkhead DNA binding domain but the CR2C. Overall, these findings demonstrate a direct connection between two key longevity pathways, FOXO3a and telomere protection. This unveils an unexpected higher level of integration in the regulation of longevity signaling pathway.



2020 ◽  
Author(s):  
Fernando R. Rosas Bringas ◽  
Sonia Stinus ◽  
Lisa Wanders ◽  
Pien de Zoeten ◽  
Marita Cohn ◽  
...  

SummaryRap1 is the main protein that binds double-stranded telomeric DNA in Saccharomyces cerevisiae. Rap1 can also bind and promote the formation of G-quadruplexes, which are thought to form at telomeres. Examination of the telomere functions of Rap1 is complicated by the fact that it also acts as a transcriptional regulator of hundreds of genes and is encoded by an essential gene. In this study, we disrupt Rap1 telomere association and G-quadruplex formation by expressing a mutant telomerase RNA subunit (tlc1-tm) that introduces mutant telomeric repeats. Remarkably, tlc1-tm cells grow as well as wild-type cells, although depletion of Rap1 at telomeres causes defects in telomere length regulation and telomere capping. We find that Rap1, Rif2, and the Ku complex work in parallel to prevent telomere degradation, and absence of all three causes lethality. The partially redundant mechanisms may explain the rapid evolution of telomere components in budding yeast species.



2019 ◽  
Author(s):  
Ann T. Sukumar ◽  
Christopher L. Williams ◽  
Celina Y. Jones ◽  
Elif Asik ◽  
Danna K. Morris ◽  
...  

ABSTRACTThe Ku heterodimer (Ku70/Ku80) binds DNA ends with high affinity but without sequence specificity and, upon binding ends created by double-stranded breaks (DSBs), initiates canonical nonhomologous end-joining (c-NHEJ). Ku also localizes to functional telomeres where its c-NHEJ activity is inhibited. Interestingly, Ku has been co-opted at telomeres across species, where it performs varied telomeric functions. In humans, Ku is essential for its role in telomere maintenance, but how it associates with human telomeres is not known. Analysis of Ku’s telomere association in different populations of cen3tel cells, which had a wide range of average telomere lengths, supported Ku’s localization at human telomeres primarily via protein-protein interaction. We also found that the Ku70 and Ku80 α5 helices, which are on opposing sides of the heterodimer and were previously implicated in Saccharomyces cerevisiae Ku’s NHEJ and telomeric functions, respectively, participated in Ku’s telomere association in human cells. While the Ku70 α5 mutant showed increased interaction with TRF2, the Ku80 α5 mutant was not impacted for TRF2 association. Interestingly, residues altered to impair Ku’s DNA end-binding function were also involved in TRF2 interaction and telomere association. Overall, our results suggest protein-protein interactions as the primary mode by which Ku associates with human telomeres.



2019 ◽  
Author(s):  
Laramie D. Lemon ◽  
Danna K. Morris ◽  
Alison A. Bertuch

ABSTRACTSaccharomyces cerevisiae telomerase, which maintains telomere length, is comprised of an RNA component, TLC1, the reverse transcriptase, Est2, and regulatory subunits, including Est1. The Yku70/Yku80 (Ku) heterodimer, a DNA end binding (DEB) protein, also contributes to telomere length maintenance. Ku binds TLC1 and telomere ends in a mutually exclusive fashion, and is required to maintain levels and nuclear localization of TLC1. Ku also interacts with Sir4, which localizes to telomeres. Here we sought to determine the role of Ku’s DEB activity in telomere length maintenance by utilizing yku70-R456E mutant strains, in which Ku has reduced DEB and telomere association but proficiency in TLC1 and Sir4 binding, and TLC1 nuclear retention. Telomere lengths in a yku70-R456E strain were nearly as short as those in ykuΔ strains and shorter than in strains lacking either Sir4, Ku:Sir4 interaction, or Ku:TLC1 interaction. TLC1 levels were decreased in the yku70-R456E mutant, yet overexpression of TLC1 failed to restore telomere length. Reduced DEB activity did not impact Est1’s ability to associate with telomerase but did result in decreased association of Est1 with the telomere. These findings suggest Ku’s DEB activity maintains telomere length homeostasis by preserving Est1’s interaction at the telomere rather than altering TLC1 levels.







2015 ◽  
pp. MCB.00746-15 ◽  
Author(s):  
Tsz Wai Chu ◽  
Yasmin D'Souza ◽  
Chantal Autexier

In most human cancer cells, cellular immortalization relies on the activation and recruitment of telomerase to telomeres. The telomere binding protein, TPP1, and the TEN domain of the telomerase catalytic subunit, TERT, regulate telomerase recruitment. TERT contains a unique ‘insertion in fingers domain' (IFD) located within the conserved reverse transcriptase domain. We report the role of specific hTERT IFD residues in the regulation of telomerase activity and processivity, recruitment to telomeres and cell survival. One hTERT IFD variant, hTERT-L805A, with reduced activity and processivity, showed impaired telomere association, which could be partially rescued by overexpression of TPP1-POT1. Another previously reported hTERT IFD mutant enzyme with similarly low levels of activity and processivity, hTERT-V791Y, displayed defects in telomere binding and was insensitive to TPP1-POT1 overexpression. Our results provide the first evidence that the IFD can mediate enzyme processivity and telomerase recruitment to telomeres in a TPP1-dependent manner. Moreover, unlike hTERT-V791Y, hTERT-V763S, a variant with reduced activity but increased processivity, and hTERT-L805A, could both immortalize limited lifespan cells, but cells expressing these two mutant enzymes displayed growth defects, increased apoptosis, DNA damage at telomeres and short telomeres. Our results highlight the importance of the IFD in maintaining short telomeres, and cell survival.



eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Alexandre Chojnowski ◽  
Peh Fern Ong ◽  
Esther SM Wong ◽  
John SY Lim ◽  
Rafidah A Mutalif ◽  
...  

Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its interaction with progerin is significantly reduced. Super-resolution microscopy revealed that over 50% of telomeres localize to the lamina and that LAP2α association with telomeres is impaired in HGPS. This impaired interaction is central to HGPS since increasing LAP2α levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects. These findings provide novel insights into the pathophysiology underlying HGPS, and how the nuclear lamina regulates proliferation and chromatin organization.



2015 ◽  
Author(s):  
Alexandre Chojnowski ◽  
Peh Fern Ong ◽  
Esther SM Wong ◽  
John SY Lim ◽  
Rafidah A Mutalif ◽  
...  


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