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Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218396 | GEO | 2022/12/12

REPOSITORIES: GEO

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Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.

Project description:Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations1,2. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.

| S-EPMC9946831 | biostudies-literature

Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis (RIP-Seq)

Project description:Interaction between ZBP1 and TERRA-derived RNA fragments

2022-12-12 | GSE218394 | GEO

Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis (RNA-Seq)

Project description:Transcriptional response to telomere shortening or dysfunction

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Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis

Project description:Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis

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Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis (RIP-Seq)

Project description:Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis (RIP-Seq)

| PRJNA903483 | ENA

Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis (RNA-Seq)

Project description:Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis (RNA-Seq)

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A Primate lncRNA Mediates Notch Signaling During Neuronal Development by Sequestering miRNA

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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IRF3 and ZBP1

Project description:This SuperSeries is composed of the SubSeries listed below.

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Chromothripsis during telomere crisis is independent of NHEJ, and consistent with a replicative origin.

Project description:Telomere erosion, dysfunction, and fusion can lead to a state of cellular crisis characterized by large-scale genome instability. We investigated the impact of a telomere-driven crisis on the structural integrity of the genome by undertaking whole-genome sequence analyses of clonal populations of cells that had escaped crisis. Quantification of large-scale structural variants revealed patterns of rearrangement consistent with chromothripsis but formed in the absence of functional nonhomologous end-joining pathways. Rearrangements frequently consisted of short fragments with complex mutational patterns, with a repair topology that deviated from randomness showing preferential repair to local regions or exchange between specific loci. We find evidence of telomere involvement with an enrichment of fold-back inversions demarcating clusters of rearrangements. Our data suggest that chromothriptic rearrangements caused by a telomere crisis arise via a replicative repair process involving template switching.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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