Junction-binding–defective Cdc13 promotes adaptive mutation and transcriptomic rewiring under telomere stress
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PROVIDER: PRJNA1308857 | ENA |
REPOSITORIES: ENA
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Project description:Telomeres protect chromosome ends from degradation and inappropriate DNA repair. In budding yeast, the telomeric protein Cdc13 binds G-rich overhangs to maintain telomere integrity. Here, we show that Cdc13 also weakly interacts with adjacent duplex DNA at the ss/dsDNA junction, a property essential for inhibiting Exo1- and Sgs1–Dna2–mediated resection. Mutation of a conserved residue (K504E) disrupts this junction recognition, impairing resection inhibition, RPA displacement, and cooperation with Ku. cdc13-K504E cells are hypersensitive to Exo1 overexpression and accumulate non-pigmented revertant colonies during chronic growth. These white colonies exhibit faster growth, altered telomere-proximal gene expression, upregulation of metabolic pathways, and increased 4N DNA content. Our findings identify a dual DNA-binding mode of Cdc13 that protects telomeres by blocking resection and regulating Ku positioning, and reveal a stress-induced adaptive state associated with telomere dysfunction.
2025-08-25 | GSE305992 | GEO
Project description:Telomeres are nucleoprotein complexes that protect the ends of eukaryotic chromosomes from being recognised as double strand breaks. When telomere structure is perturbed, a co-ordinated series of events to promote arrest of the cell cycle is rapidly initiated so that cells carrying damaged telomeres do not continue to divide. In order to better understand the eukaryotic response to telomere damage, we employed budding yeast strains harbouring a temperature sensitive allele of an essential telomere capping gene (cdc13-1) and conducted a transcriptomic study of the genome-wide response to uncapped telomeres. We show that telomere uncapping in cdc13-1 strains is associated with the differential expression of over 1100 genes and has features in common with the responses to DNA damage, diverse environmental stresses and, as expected, the absence of telomerase. The transcriptomic response to telomere uncapping includes many genes with known roles in telomere function and some features that appear to be unique. BNA2 is the second most highly up-regulated gene upon telomere uncapping in cdc13-1 strains and is required for the biosynthesis of NAD+. We have shown that deletion of BNA2 and other genes involved in NAD+ synthesis, suppresses the temperature sensitivity of cdc13-1 strains. NAD+ synthetic genes may therefore play previously unknown roles in the cellular response to telomere uncapping.
2010-02-24 | E-MEXP-1551 | biostudies-arrayexpress
Project description:Histones of heterochromatin are deacetylated in yeast and methylated in more complex eukaryotes to regulate heterochromatin structure and gene silencing. Here, we report that histone H2A phosphorylated at serine 129 (γH2A) in Saccharomyces cerevisiae is a conceptually new type of heterochromatin modification that functions downstream of silent chromatin assembly. We show that γH2A is enriched throughout yeast telomeric and silent mating locus (HM) heterochromatin where γH2A results from the action of kinases Tel1 and Mec1. Interestingly, mutation of γH2A has no apparent effect on the binding of Sir (silent information regulator) complex or on gene silencing. In contrast, deletion of SIR3 abolishes the formation of γH2A at heterochromatin. To address the function of γH2A, we used a ∆rif1 mutant strain in which telomeres are excessively elongated to show that γH2A is required for the optimal recruitment of Cdc13, a regulator of telomere elongation, and for telomere elongation itself. Thus, a histone modification that parallels Sir3 protein binding is shown here to be dispensable for the formation of a silent structure but is important for a crucial heterochromatin-specific downstream function in telomere homeostasis.
2011-01-05 | GSE21814 | GEO
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.
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Project description:Here we found that ILF3 prefers to bind telomere R-loops and protects telomere from aberrant homologous recombination. ILF3 knockout induces TERRA aggregation onto telomere and activates telomere DNA damage response (DDR). Furthermore, ILF3 deficiency disrupts telomere homeostasis and induces abnormal ALT-mediated telomere lengthening
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Project description:We used microarrays to analyze the prevalence of signalling induced by acute telomere dysfunction (as induced by TRF2DBDM expression = Dataset 1) and in TERC- compared to TERC+ HCC (Dataset 2). Keywords: acute telomere dysfunction, hepatocellular cancer
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Project description:We examined differential expression of genes within 10MBs of telomeres in myoblasts with long or short telomeres We offer telomere looping with telomere length as a partial mechanistic explanation for the changes gene expression that is observed.
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