Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis

Abstract

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.

Z-flipon variants reveal the many roles of Z-DNA and Z-RNA in health and disease

“…Interestingly, we did not detect a substantial overlap with regions of G-banding or with high recombination frequencies, negating a number of previous proposals made without experimental support ( Fig S5 ) ( Rich et al, 1984 ). We do observe a marked overlap with subtelomeric regions that was quite unanticipated and is of interest given the role subtelomeric RNAs play in inducing ZBP1-dependent cell death during replicative stress ( Nassour et al, 2023 ).…”

Fate of telomere entanglements is dictated by the timing of anaphase midregion nuclear envelope breakdown

“…In human cells, which undergo complete mitotic NE breakdown, telomere fusions that elicit dicentric chromosomes lead to the formation of NE bridges between daughter cells that persist into the next cell cycle; in the subsequent interphase, bridge rupture leads to untimely cytoplasmic exposure with profound consequences for chromosome segregation, including chromothripsis and kataegis. Moreover, as cells harboring telomere fusions traverse mitosis, the presence of telomeric DNA and RNA in the cytoplasm leads to autophagy and activation of innate immune signaling, respectively [59][60][61][62][63][64] . Our work demonstrates that different types of telomeric associations trigger different resolution processes.…”

Tumor necrosis factor-alpha mediates the association between telomere length and kidney dysfunction in patients with hypertension

“…Animal studies have also shown that TNF-α levels are increased in animals with shorter telomeres [28]. An in vitro experiment revealed that short telomeres can mediate additional downstream activation of ZBP1(S), via TERRA, to form ZBP1 laments on the mitochondria, thereby promoting the in ammatory cycle [29]. In contrast, other animal experiments have shown that in ammation and oxidative stress signi cantly contribute to renal damage associated with hypertension, and cytokines, such as interferon-γ, TNF-α, and IL-17, affect Na+/H + exchangers in the kidney [16].…”