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The nonsense-mediated mRNA decay (NMD) pathway safeguards telomeres in pluripotent stem cells

ABSTRACT: Telomeres are repetitive DNA sequences that cap chromosome ends and are bound by the Shelterin complex to prevent aberrant activation of DNA damage signaling. While TRF2, a core Shelterin component, is essential for repressing non-homologous end joining (NHEJ) in somatic cells, it is dispensable for telomere protection in mouse embryonic stem cells (mESCs). To uncover compensatory pathways, we performed a synthetic lethal genome-wide CRISPR/Cas9 screen in TRF2-deficient mESCs and identified multiple components of the nonsense-mediated mRNA decay (NMD) pathway as essential for cell viability. We show that NMD promotes telomere protection by regulating the abundance of TRF1, another Shelterin component, at telomeres. Specifically, NMD limits the accumulation of a TRF1 mRNA isoform that encodes a dominant-negative protein variant. These findings reveal a previously unrecognized role for mRNA surveillance in maintaining telomere integrity in pluripotent cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE300187 | GEO | 2026/02/10

REPOSITORIES: GEO

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A CPC-shelterin-BTR axis regulates mitotic telomere deprotection

Project description:Telomeres prevent ATM activation by sequestering chromosome termini within telomere loops (t-loops). Mitotic arrest promotes telomere linearity and a localized ATM-dependent telomere DNA damage response (DDR) through an unknown mechanism. Using unbiased interactomics, biochemical screening, molecular biology, and super-resolution imaging, we found that mitotic arrest-dependent (MAD) telomere deprotection requires the combined activities of the Chromosome passenger complex (CPC) on shelterin, and the BLM-TOP3A-RMI1/2 (BTR) complex on t-loops. During mitotic arrest, the CPC component Aurora Kinase B (AURKB) phosphorylated both the TRF1 hinge and TRF2 basic domains. Phosphorylation of the TRF1 hinge domain enhances CPC and TRF1 interaction through the CPC Survivin subunit. Meanwhile, phosphorylation of the TRF2 basic domain promotes telomere linearity, activates a telomere DDR dependent on BTR-mediated double Holliday junction dissolution, and leads to mitotic death. We identify that the TRF2 basic domain functions in mitosis-specific telomere protection and reveal a regulatory role for TRF1 in controlling a physiological ATM-dependent telomere DDR. The data demonstrate that MAD telomere deprotection is a sophisticated active mechanism that exposes telomere ends to signal mitotic stress.

2025-01-28 | PXD043281 | Pride

ZNF524 directly binds telomeres and supports their integrity via TRF2/RAP1

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 consists of six proteins (TRF1, TRF2, RAP1, POT1, TPP1 and TIN2) and blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. While shelterin does not work autonomously, additional direct telomere binding proteins have been described to function in a supplementary role. We here describe ZNF524, a zinc finger protein that directly binds to 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 the other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, we identified ZNF524 as a direct telomere binding protein and propose that ZNF524 is involved in the maintenance of telomere integrity by promoting TRF2/RAP1 subcomplex binding.

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ZNF524 directly binds telomeres and supports their integrity via TRF2/RAP1

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The human TTAGGG Repeat Factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats

Project description:The study of the proteins that bind to telomeric DNA in mammals has provided a deep understanding of the mechanisms of chromosome-end protection. However, very little is known on the binding of these proteins to nontelomeric DNA sequences. The TTAGGG DNA repeat proteins 1 and 2 (TRF1 and TRF2) bind to mammalian telomeres as part of the shelterin complex and are essential for maintaining chromosome end stability. In this study, we combined chromatin immunoprecipitation with high-throughput sequencing to map at high sensitivity and resolution, the human chromosomal sites to which TRF1 and TRF2 bind. While most of the identified sequences correspond to telomeric regions, we showed that these two proteins also bind to extratelomeric sites. The vast majority of these extra-telomeric sites contains interstitial telomeric sequences (or ITSs). However we also identified non-ITS sites, which are also satellite DNA but the ones mainly constitutive of centromeric and pericentromeric regions. Interestingly, the TRF-binding sites are often located in the proximity of genes or within introns. We propose that, by binding to extratelomeric sequences, TRF1 and TRF2 couple the functional state of telomeres to the long-range organization of chromosomes and gene regulation networks. ChIP-SEQ experiment of transformed human fibroblast BJ cells with 3 antibodies (1 monoclonal anti-TRF1, 1 monoclonal anti-TRF2, 1 polyclonal anti-TRF2) and a negative control (proteinG without antibody used as the ChIP background)

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Depletion of the TRF1 telomere-binding protein leads to leaner mice with improved metabolism

Project description:TRF1, a component of the telomere shelterin complex, plays crucial roles in telomere protection, telomere length regulation, and stemness. Here, we describe a previously unknown connection between TRF1 and metabolism. Telomere attrition has been linked to obesity. Our study reveals that Trf1-deficient mice exhibit a leaner phenotype, reduced adiposity, and improved glucose tolerance, even when subjected to a high-fat diet, independently of telomere shortening. These findings uncover a previously unknown role of TRF1 in regulating metabolism. Our research not only contributes to the understanding of obesity onset but also positions TRF1 as a potential therapeutic target for combating metabolic syndrome.

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A cell cycle switch in TRF2 controls t-loop dynamics and DNA secondary structure resolution across the genome

Project description:Telomere end-protection by the shelterin complex prevents DNA damage signalling and promiscuous repair at chromosome ends. Evidence suggests that the 3’ single-stranded telomere end can assemble into a lasso-like t-loop configuration, which has been proposed to safeguard chromosome ends from being recognized as DNA double strand breaks. Mechanisms must also exist to transiently disassemble t-loops to allow faithful telomere replication and to permit telomerase access to the 3’-end to solve the end replication problem. However, the regulation and physiological importance of t-loops in end-protection remains uncertain. Here, we identify a CDK phosphorylation site in the shelterin subunit, TRF2 (Ser365), whose dephosphorylation in S-phase by the PP6C/R3 phosphatase provides a narrow window during which the helicase RTEL1 is able to transiently access and unwind t-loops to facilitate telomere replication. Re-phosphorylation of TRF2 on Ser365 outside of S-phase is required to release RTEL1 from telomeres, which not only protects t-loops from promiscuous unwinding and inappropriate ATM activation, but also counteracts replication conflicts at DNA secondary structures arising within telomeres and across the genome. Hence, a phospho-switch in TRF2 coordinates assembly and disassembly of t-loops during the cell cycle, which protects telomeres from replication stress and an unscheduled DNA damage response.

2019-11-25 | PXD014843 | Pride

The human TTAGGG Repeat Factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats

2011-05-04 | GSE26005 | GEO

Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is associated with shelterin complex at interstitial telomeric sites

Project description:Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is primarily expressed in neuronal cells and neuroendocrine cells. It is a multifunctional protein involved in deubiquitination, ubiquitination, and ubiquitin homeostasis. UCHL1 has been associated with various diseases, including many cancers, but its specific roles are disputed and still generally undetermined. Herein, we demonstrate that UCHL1 is associated with genomic DNA in certain prostate cancer cell lines, including DU 145 cells derived from a brain metastatic site, and in HEK293T embryonic kidney cells with a neuronal lineage. Chromatin immunoprecipitation and sequencing revealed that UCHL1 localizes to TTAGGG repeats at telomeres and interstitial telomeric sequences, as do TRF1 and TRF2, components of the shelterin complex. A weak or transient interaction between UCHL1 and the shelterin complex was confirmed by immunoprecipitation and proximity ligation assays. UCHL1 and TERF2IP, also a component of the shelterin complex, were bound to the nuclear scaffold. UCHL1 may play a role in regulating gene expression by affecting the stabilization of the shelterin proteins or influencing nuclear targeting. As several shelterin proteins (TRF1, TRF2, POT1 and TERF2IP) are ubiquitinated, UCHL1 may have a role in regulating the stability of these proteins. UCHL1 may also regulate the nuclear location of shelterin-associated genomic regions.

2018-02-23 | GSE97111 | GEO

RNA-seq, ChIP-seq and TERRA CHIRT-seq from p53-/- iPS infected with a lentiviral virus carrying a control scrambled shRNA or shRNA against TRF1

Project description:The mechanisms that regulate pluripotency and cell fate are still largely unknown. Here, we show that the Telomere Repeat Binding Factor 1 (TRF1), a component of the shelterin telomere protection complex, regulates genome-wide binding of polycomb to stem cell and pluripotency genes, thereby exerting vast epigenetic changes that contribute to maintain embryonic stem cells in a naïve state. We further show that TRF1 mediates these effects by regulating TERRA, the long-non-coding RNAs transcribed from telomeres and that are part of the telomeric chromatin. In particular, we find that TERRAs are enriched at polycomb and stem cell genes in pluripotent cells and that TRF1 abrogation results in increased TERRA levels and a higher binding of TERRA to those genes, an event that is coincidental with TRF1-dependent induction of cell-fate programs and loss of the naïve state. These results are consistent with a model in which TERRA recruits polycomb to genes important for pluripotency and differentiation in a manner that is dependent on TRF1. These unprecedented findings explain the long-standing observation that TRF1 is one of the most upregulated genes during induction of pluripotency and it is essential for the induction and maintenance of pluripotency.

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ZNF524 directly interacts with telomeric DNA and supports telomere integrity

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.

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