Telomeric 8-Oxoguanine Drives Rapid Premature Senescence in the Absence of Telomere Shortening
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PROVIDER: PRJNA733186 | ENA |
REPOSITORIES: ENA
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Project description:Oxidative stress is a primary cause of cellular senescence and contributes to the pathogenesis of numerous human diseases. Oxidative damage to telomeric DNA is proposed to trigger premature senescence by accelerating telomere shortening. Here we tested this model directly using a precision tool to produce the common base lesion 8-oxoguanine (8oxoG) exclusively at telomeres in human fibroblast and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence. Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and delayed mitotic DNA synthesis at telomeres, indicative of impaired replication. Based on our results we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions which drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.
2022-05-26 | GSE175686 | GEO
Project description:Telomere shortening can cause detrimental diseases and contribute to aging. It occurs due to the end replication problem in cells lacking telomerase. In addition, recent evidence revealed that telomere shortening can be attributed to difficulties of the semi-conservative DNA replication machinery to replicate through the bulk of telomeric DNA repeats. To investigate telomere replication in a comprehensive manner, we developed QTIP-iPOND, which enables purification of the proteins that associate with telomeres during their replication. We identify in addition to the core replisome a large number of proteins that specifically associate with telomere replication forks and validate their importance.
2021-11-03 | PXD018712 | Pride
Project description:Gene expression changes of UC-model organoids derive from human colon indcued by telomere enlongation was assessed by Madecassoside treatemt (telomerase activator). Gene expression changes of human colon organoids induced by telomere shortening was assessd by MST-312 treatment (telomerase inhibitor).
2021-06-24 | GSE175994 | GEO
Project description:Background. Telomeric small RNAs related to PIWI-interacting RNAs (piRNAs) have been described in various eukaryotes; however, their role in germline-specific telomere function remains poorly understood. Using a Drosophila model, we performed an in-depth study of the biogenesis of telomeric piRNAs and their function in telomere homeostasis in the germline. Results To fully characterize telomeric piRNA clusters, we integrated the data obtained from analysis of endogenous telomeric repeats, as well as transgenes inserted into different telomeric and subtelomeric regions. The small RNA-seq data from strains carrying telomeric transgenes demonstrated that all transgenes belong to a class of dual-strand piRNA clusters; however, their capacity to produce piRNAs varies significantly. Rhino, a paralog of heterochromatic protein 1 (HP1) expressed exclusively in the germline, is associated with all telomeric transgenes, but its enrichment correlates with the abundance of transgenic piRNAs. It is likely that this heterogeneity is determined by the sequence peculiarities of telomeric retrotransposons. In contrast to the heterochromatic non-telomeric germline piRNA clusters, piRNA loss leads to a dramatic decrease in HP1, Rhino, and trimethylated histone H3 lysine 9 in telomeric regions. Therefore, the presence of piRNAs is required for the maintenance of telomere chromatin in the germline. Moreover, piRNA loss causes telomere translocation from the nuclear periphery toward the nuclear interior but does not affect telomere end capping. Analysis of the telomere-associated sequences (TASs) chromatin revealed strong tissue specificity. In the germline, TASs are enriched with HP1 and Rhino, in contrast to somatic tissues, where they are repressed by Polycomb group proteins. Conclusions piRNAs play an essential role in the assembly of telomeric chromatin, as well as in nuclear telomere positioning in the germline. Telomeric arrays and TASs belong to a unique type of Rhino-dependent piRNA clusters with transcripts that serve simultaneously as piRNA precursors and as their only targets. Telomeric chromatin is highly sensitive to piRNA loss, implying the existence of a novel developmental checkpoint that depends on telomere integrity in the germline.
2018-07-12 | GSE98981 | GEO
Project description:To determine whether telomere shortening in thyroid tumors delineates gene expression of subtelomeric regions, we performed RNA sequencing in a set of tumors (n = 15) and compare gene expression profiles of subtelomeric and non-subtelomeric genes between short telomere tumors and normal telomere tumors. We defined as subtelomeric genes, those located within the 5 megabase windows (Mb) adjacent to the telomeres.
2022-08-24 | GSE193623 | GEO
Project description:Telomeres play crucial roles during tumorigenesis inducing cellular senescence upon telomere shortening and extensive chromosome instability during telomere crisis. However, it has not been investigated if and how cellular transformation and oncogenic stress alters telomeric chromatin composition and function. Here we transform human fibroblasts by consecutive transduction with vectors expressing hTERT, the SV40 early region and activated H-RasV12. Pairwise comparisons of the telomeric proteome during different stages of transformation reveals upregulation of proteins involved in chromatin remodeling, DNA repair and replication at chromosome ends. Depletion of several of these proteins induces telomere fragility indicating their roles in replication of telomeric DNA. Depletion of SAMHD1, which has reported roles in DNA resection and homology directed repair, leads to telomere breakage events in cells deprived of the shelterin component TRF1. Thus our analysis identifies factors, which accumulate at telomeres during cellular transformation to promote telomere replication and repair, resisting oncogene-borne telomere replication stress.
2018-07-13 | PXD010088 | Pride
Project description:We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukaemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from individuals with the shortest telomeres revealed limited numbers of repeats at the breakpoint, sub-telomeric deletion and microhomology. Array-CGH analysis of individuals displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. Array CGH was undertaken on six individuals (five CLL stage C and one stage A) that displayed evidence of telomere dysfunction, and four (three CLL stage A and one stage B) that displayed longer and apparently stable telomeres.
2010-05-28 | E-GEOD-22016 | biostudies-arrayexpress
Project description:Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. We here describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.
2023-10-21 | PXD043084 | Pride
Project description:We asked whether telomere shortening impairs differentiation of ESCs into germ cell lineage. Terc-/- ESCs were used to investigate the effects of short telomeres on germ cell specification by in vitro differentiation. Short telomeres greatly reduced induction of PGCLCs from ESCs. Mechanistically, short telomeres resulted in excessive chromatin accessibility, which in turn activated the genes regulated by chromatin. Notably, Fst overexpression reduced BMP-Smad signaling and thus induction of PGCLCs, meanwhile upregulation of MAPK signaling pathway increase somatic lineage differentiation in short telomeres sampels. Moreover, knockin of Terc gene by CRISPR/Cas9 in Terc-/- ESCs restored telomere length and normal gene expression profile, and rescued PGCLC induction, revealing important roles of telomeres in PGC fate decision.
2022-08-31 | GSE157303 | GEO
Project description:We asked whether telomere shortening impairs differentiation of ESCs into germ cell lineage. Terc-/- ESCs were used to investigate the effects of short telomeres on germ cell specification by in vitro differentiation. Short telomeres greatly reduced induction of PGCLCs from ESCs. Mechanistically, short telomeres resulted in excessive chromatin accessibility, which in turn activated the genes regulated by chromatin. Notably, Fst overexpression reduced BMP-Smad signaling and thus induction of PGCLCs, meanwhile upregulation of MAPK signaling pathway increase somatic lineage differentiation in short telomeres sampels. Moreover, knockin of Terc gene by CRISPR/Cas9 in Terc-/- ESCs restored telomere length and normal gene expression profile, and rescued PGCLC induction, revealing important roles of telomeres in PGC fate decision.
2022-08-31 | GSE157301 | GEO