Telomeres as hotspots for innate immunity and inflammation

Abstract

Aging is marked by the gradual accumulation of deleterious changes that disrupt organ function, creating an altered physiological state that is permissive for the onset of prevalent human diseases. While the exact mechanisms governing aging remain a subject of ongoing research, there are several cellular and molecular hallmarks that contribute to this biological process. This review focuses on two factors, namely telomere dysfunction and inflammation, which have emerged as crucial contributors to the aging process. We aim to discuss the mechanistic connections between these two distinct hallmarks and provide compelling evidence highlighting the loss of telomere protection as a driver of pro-inflammatory states associated with aging. By reevaluating the interplay between telomeres, innate immunity, and inflammation, we present novel perspectives on the etiology of aging and its associated diseases.

1. Protective properties of telomeres

The linear ends of eukaryotic chromosomes are constantly at risk of being mistaken for DNA breaks, creating a continuous threat to genome integrity and cell viability. Telomeres solve this end protection problem by employing diverse mechanisms capable of shielding chromosome termini from DNA damage surveillance and repair pathways [1–3]. Several factors, however, can compromise the functionality of this protective mechanism. First, telomeres in human somatic cells undergo gradual shortening due to the unidirectional nature of DNA polymerase and nucleolytic processing events during each round of cell cycle division [4–8]. In addition, replication forks are subject to stalling and collapsing as they navigate through telomeric sequences, resulting in incomplete replication and DNA sequences loss [9–12]. Last, the distinctive composition of telomeres, characterized by G-rich repeat sequences, renders them susceptible to oxidative DNA damage and buildup of persistent lesions [13–15], a process that has been recently termed TelOxidation [16]. This vulnerability extends to post-mitotic cells that do not undergo cell division, including cardiomyocytes, neurons, and osteoblasts [17] among others. The cumulative impact of these events can compromise telomere protection, resulting in premature aging syndromes and elevated susceptibility to cancer.

In humans, telomeres consist of repeated hexanucleotide sequences (5′-TTAGGG-3′) spanning several kilobases and terminating with a single-stranded (ss) 3′ G-overhang [18,19]. Telomeric DNA protects chromosome ends through its interaction with the six-subunit shelterin complex: TRF1 and TRF2 form homodimers and bind to double-stranded DNA [20,21], while POT1 specifically binds to ssDNA [22,23]. TIN2 and TPP1 act as connectors between the DNA-binding proteins [24–27], and RAP1 associates with TRF2 [28]. Among the shelterin proteins, TRF2 exhibits a remarkable capability to wrap DNA around itself [29,30] and promote Holliday junction formation [31–33]. These unique properties enable TRF2 to effectively remodel telomeric DNA into a closed t-loop configuration, where the 3′ overhang invades the adjacent double-stranded region [34]. This arrangement, first observed through electron microscopy [35] and later confirmed using super-resolution light microscopy [36], provides a first layer of protection by hiding the telomere terminus from DNA damage response factors that rely on exposed DNA ends. Other protective mechanisms include POT1 blocking RPA access to ssDNA to prevent ATR kinase activation [37–39] (Fig. 1A) and TRF1 preventing replication fork stalling during telomere replication [23,40]. In the absence of shelterin, telomeres are exposed to DNA damage surveillance and chromosome ends become inappropriately processed by three distinct and cell cycle-dependent repair pathways: classical non-homologous end joining (c-NHEJ), alternative end joining (alt-EJ) and homology-directed repair (HDR) [2] (Fig. 1). These repair activities set in motion a cascade of deleterious events ranging from chromosomal rearrangements, decrease of cellular fitness, to innate immune response and inflammation, each contributing to the characteristic features of aging.

Fig. 1. DNA repair pathways at deprotected telomeres.

A) ssDNA activates the ATR kinase pathway. B) DSBs are recognized either by Ku heterodimer or MRN complex and activate the ATM kinase pathway. This triggers local phosphorylation of multiple ATM substrates in the surrounding chromatin, most notably the histone variant H2AX and the recruitment of additional DDR mediators, such as 53BP1 and MDC1, at the break site. These modifications give rise to TIF, macroscopic structures that mark sites of deprotected telomeres. This signaling switches from phosphorylation to ubiquitination through the recruitment of E3 ligases, including RNF8 and RNF168, resulting in the ubiquitination of several proteins, including H2A/H2AX. C) During c-NHEJ, broken ends are rapidly bound by Ku, followed by the recruitment and activation of the DNA-PKcs. Broken DNA ends are joined by DNA ligase IV. Depletion of TRF2 provokes undesired c-NHEJ activity at telomeres, potentially resulting in chromosomal end-to-end fusions. D) MRN/CtIP-mediated short-range resection disrupts the c-NHEJ pathway by displacing Ku from DNA ends and exposes short microhomologies of 2–20 bp (green boxes) required for alt-EJ. This repair process is contingent on PARP1 and Polθ and is finalized by DNA ligase III. E) Extensive resection is executed by EXO1 or combined action of BLM helicase and DNA2 nuclease. Generated 3’ ssDNA overhangs, rapidly coated with RPA heterotrimer, facilitate either inter- or intratelomeric strand invasion and recombination. This invasion results in break-induced telomere synthesis via a noncanonical Polδ-PCNA-RFC1 replisome. Formed D-loop can be resolved by the SMX endonuclease complex, causing crossover events without telomere elongation (telomeric sister chromatid exchange (T-SCE), indicated by yellow telomeres), or dissolved by the BTR complex, leading to telomere extension without crossover. Aberrant excision of T-loops formed by intratelomeric recombination via SLX4 or XRCC3 and NBS1 repair proteins can result in accumulation of ECTRs and rapid telomere shortening. Shelterin proteins and auxiliary factors, which inhibit specific stages of DNA repair mechanisms at deprotected telomeres, are highlighted with red boxes. (1) TPP1-POT1 complex represses ATR signaling by blocking RPA association with telomeric overhang. (2) TRF2 aids in forming the protective t-loop structure, shielding chromosome ends from DNA sensors. In addition, TRF2 inhibits Ku heterodimerization, thereby preventing c-NHEJ activation. (3) TRF2 through its iDDR domain impedes the recruitment of RNF168, limiting downstream signaling events. (4) Shelterin and the Ku heterodimer act in coordinated fashion to suppress alt-EJ. (5) components TRF2, RAP1, and POT1, in conjunction with Ku, impede sequence exchange between sister chromatid telomeres. (6) During the S phase, TRF2 recruits RTEL1 to unwind the t-loop, shielding it from cleavage by SLX4. Furthermore, TRF2 inhibits t-loop excision by suppressing NBS1–XRCC3 activity.

The sequence-independent c-NHEJ pathway is directed by the Ku70-Ku80 heterodimer (Ku) and engages the catalytic subunit of DNA-PKcs to coordinate end processing and produce blunt ended substrates for the DNA ligase IV complex [41] (Fig. 1C). On the other hand, alt-EJ requires microhomologies exposed by MRN-CtIP-mediated resection [42] and depends on PARP1, DNA polymerase theta, and DNA ligase III (Fig. 1D). Unlike intra-chromosomal breaks, the prevention of end-joining pathways at telomeres is essential. This is primarily achieved through TRF2-mediated t-loop formation while suppressing ATM activation [43,44], as well as the iDDR region of TRF2 inhibiting the recruitment of E3 ubiquitin ligase RNF168 [45] (Fig. 1B). Furthermore, the interaction between TRF2 and the α-helix 5 domain of Ku70—which mediates the heterotetramerization of Ku—prevents the synapsing of chromosome ends [46]. The unique sequence composition of telomeres makes minor resections highly favorable for alt-EJ, but research in mice reveals that this repair pathway only reaches full activity when both Ku and all shelterin components are missing [47]. During end-joining activities at telomeres, inter-chromosomal fusions are primarily driven by LIG4-dependent c-NHEJ [48,49] while intra-chromosomal fusions between sister chromatids rely on LIG3-mediated alt-EJ [50,51] (Fig. 1C, D). The subsequent formation of fused chromosomes, along with lagging chromosomes and acentric fragments that fail to incorporate into daughter nuclei during mitosis, leads to aneuploidy and multiple features of genome instability.

As cells progress through S and G2 phase, the HDR pathway becomes the primary strategy for handling DSBs and replication stress (Fig. 1E). This is facilitated by extensive long-range resection, mediated either by EXO1 or the BLM-DNA2 complex [52]. The resulting extended 3’ ssDNA tails provide a platform for the BRCA2-PALB2-BRCA1 complex to initiate the formation of RAD51 presynaptic filaments, required for strand invasion and homology search [53]. At deprotected telomeres, the invading strand can originate from the same (intra-chromosomal) or a different (inter-chromosomal) chromosome, and in both settings, it participates in break-induced telomere synthesis (BITS), a process contributing to the alternative lengthening of telomeres (ALT). Recombination intermediates can be either resolved by the BTR complex, promoting telomere extension without exchange, or directly cleaved by structure-specific nucleases like the SMX complex, resulting in telomeres with exchanged sequences [54]. The coordinated action of POT1, TRF2, and the Ku complex protects telomeres from unequal chromatid exchanges [38,55,56], with POT1 binding to ssDNA hindering RPA access to the telomeric overhang and preventing ATR signaling [57](Fig. 1A). A compromised TRF2 or Ku complex leads to aberrant HDR at telomeres, resulting in t-loop excision mediated by XRCC3, NBS1, and SLX4, accelerated telomere loss, and extrachromosomal telomeric repeats (ECTRs) [58,59]. The RTEL1 protein, an accessory component of the shelterin complex, mitigates this process by unwinding the t-loops, thus adding an additional layer of regulation in maintaining telomere integrity [60]. While HDR activities at telomeres may appear less harmful than end-joining, they can give rise to telomere sister chromatid exchanges (T-SCEs) [61], aberrant t-loop excisions leading to ECTRs, and recombination events that affect telomere length dynamics and jeopardize cellular viability (Fig. 1E).

2. Telomere-associated molecular patterns

Recent research has revealed that telomere deprotection serves as an intrinsic stimulus for innate immune sensing and signaling pathways, causing so-called sterile inflammation in the absence of pathogen infection. The connection between telomeres and inflammation is further supported by studies utilizing telomerase-null zebrafish [62] and mouse models [63–65], which exhibit accelerated telomere shortening, premature aging, and heightened inflammation. In humans, individuals with short telomere syndromes demonstrate premature aging and inflammation [66–68], while those with chronic inflammatory conditions often display compromised telomere protective mechanisms [69–72]. This section explores the molecular pathways that interconnect telomere biology and innate immunity, illuminating their dynamic interplay within the context of chronic age-related conditions.

2.1. Cytosolic DNA-sensing through cGAS

Innate immunity forms the initial line of defense against invading pathogens, priming the subsequent induction of an adaptive immune response [73]. This pathway relies on specialized sensors called pattern-recognition receptors (PRRs) capable of detecting a variety of pathogen-specific molecules, including lipids, sugars, and nucleic acids (NA), commonly referred to as danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) [74]. Self-NA resulting from cellular processes such as replication stress [75], genomic or mitochondrial DNA damage [76,77], or endogenous retroelement (ERE) activation [78] have been also identified as molecular patterns capable of triggering immune surveillance sensors and contributing to sterile inflammation.

Sensing cytosolic DNA is a fundamental aspect of innate immunity, with major sources including those acquired from the extracellular microenvironment or pathogens such as DNA viruses, retroviruses, bacteria, and parasites, as well as self-DNA leaking from the mitochondria and nucleus [79]. The nuclear envelope (NE) acts as a crucial regulatory barrier to prevent an aberrant innate immune response to host DNA molecules. However, during mitosis, cell migration, or other circumstances, the disintegration of the NE can lead to the mislocalization of DNA to the cytosol, triggering its subsequent detection by innate immune surveillance mechanisms. A key outcome of activating this signaling pathway is the generation of soluble mediators such as inflammatory cytokines and type I interferon (IFNs), which stimulate the production of IFN-stimulated genes (ISGs) with diverse antiviral, antitumor, and immunoregulatory properties [80].

Upon loss of telomere protection, DNA ends become susceptible to c-NHEJ and alt-EJ repair pathways, leading to the formation of three distinct types of fused chromosomes that fail to properly segregate during anaphase [50,81–84] (Fig. 2A). Genomic fusions take place between telomeres with non-telomeric loci, while inter-chromosomal fusions result in dicentric chromosomes, each retaining a functional centromere. Intra-chromosomal fusions occur between sister chromatids and generate pseudo-dicentric chromosomes, where the sister centromeres are correctly attached to opposing spindle poles during mitosis but remain linked at the fused end (Fig. 1C, D) [85].

Fig. 2. Telomere-associated molecular patterns.

Telomere-driven innate immunity involves the activation of interconnected DNA- and RNA-sensing pathways. A) Deprotected telomeres result in chromosome fusion and formation of dicentric chromosomes. Tension across the centromeres of a dicentric chromosome can lead to chromosomal bridge formation, which is often resolved via fragmentation. Broken chromosome fragments lacking centromere may be mis-segregated, resulting in formation of one or more MN. MN can also emerge from lagging chromosomes that detach from both centromeres and are left behind at anaphase. These MN, characterized by an unstable nuclear envelope provoke cGAS activation upon envelope rupture. DNA bridges may endure past anaphase forming a link between two newly assembled daughter nuclei. These NPBs share similar nuclear envelope defects with micronuclei, leading to cGAS-dependent innate immune response. B) ECTRs, products of telomere trimming and HDR activity, may exhibit linear or circular configurations. The latter includes t-circles (both strands), C-circles (entire C-rich circle with a G-rich primer), or G-circles (complete G-rich circle with a C-rich primer). When released into cytoplasm, ECTRs can activate cGAS pathway. C) TERRA is a long non-coding RNA transcribed by RNA Polymerase II from subtelomeric regions toward chromosome ends, using the C-rich strand as a template. The cytosolic TERRA molecules can adopt multiple structures, such as ssRNA, G-quadruplex configurations, or RNA:DNA hybrids excised from telomeric R-loops. All TERRA species have the potential to provoke an innate immune response. D) In the cytosol, telomere-derived dsDNA species are recognized and bound by cGAS, activating STING. On the other hand, ZBP1 interacts with cytosolic TERRA, triggering MAVS-dependent signaling. Both pathways induce the transcription of interferon genes and proinflammatory cytokines via the TBK1-IRF3 and IKK-NFκB signaling cascades.

During anaphase, dicentric chromatids are pulled apart, creating a DNA bridge that can break by the spindle pulling forces, only to later rejoin over multiple breakage-fusion-bridge (BFB) cycles [86]. This catastrophic mutational process drives rapid genome evolution during tumorigenesis and is often accompanied by the generation of acentric fragments, forming one or more micronuclei (MN) at the end of mitosis [87,88] (Fig. 2A). It has also been described that, instead of breaking, dicentric chromosomes involved in anaphase bridges are sometimes detached from the two centrosomes, left behind at anaphase, and sequestered into MN [89] (Fig. 2A). Alternatively, DNA bridges can persist and extend beyond cytokinesis, carrying into the subsequent G1 phase [90]. The chromatin bridges linking the newly forming nuclei experience stretching due to cell migration and can reach hundreds of microns in length before eventually breaking (Fig. 2A). Transient accumulation of actin and myosin occurs at the bridge, and defects in myosin activation or actin assembly delay chromatin bridge breakage, suggesting that the tension generated by actomyosin force during cell division is required to break chromatin bridges [91]. In addition to DNA rupture through mechanical force, the TREX1 exonuclease is implicated in severing chromatin bridges [90]. This process involves a temporary rupture of the NE and loss of the nuclear permeability barrier, enabling cytoplasmic nucleases such as TREX1 to access chromatin and generate ssDNA fragments, which may facilitate breaks as DNA becomes increasingly stretched and fragile [90]. In both settings, the rupture of the chromatin bridge could also lead to the generation of acentric chromosome fragments distributed into MN.

Fused telomeres engage innate immunity through a mechanism involving the loss of cellular compartmentalization and the exposure of genomic DNA to cytoplasmic components including cGAS, an innate immune sensor that recognizes a wide range of cytoplasmic double-stranded DNA (dsDNA) species of both foreign and self-origin in a length-dependent but sequence-independent manner [92] (Fig. 2A). MN arising at mitotic exit, due to the incomplete partitioning of acentric chromosomal fragments or lagging chromosomes into daughter cells, frequently experience structural defects in the underlying lamina and nuclear pore complexes, collectively leading to the spontaneous collapse of the NE [93,94]. These disruptions not only impact crucial processes within MN, including DNA replication and repair, but also facilitate the access of cGAS to micronuclear DNA [95] (Fig. 2A). Further, persistent chromatin bridges during interphase induce a transient NE rupture during interphase, mixing nuclear and cytoplasmic components, and granting access to cGAS to the bridge DNA [90] (Fig. 2A). The precise connection between NE rupture and cGAS sensing remains unclear. Recent research indicates that a fraction of cGAS is located within the nucleus, where it is unable to oligomerize when tethered to nucleosomes [94,96–102]. The role of chromatin in restricting cGAS enzymatic activity suggests that NE rupture alone may not be sufficient to trigger cGAS activation, and additional factors such as DNA damage caused by exposure to cytoplasmic nucleases could alter chromatin state and facilitate cGAS activation. In line with this idea, genetic abnormalities in the histone pre-mRNA processing complex result in chromatin without linker histones, leading to cGAS stimulation and subsequent emergence of an IFN response [102].

In addition to the exposed DNA at the chromatin bridge and MN, ECTRs released into the cytoplasm can be also recognized by cGAS [103] (Fig. 2B). ECTRs manifest in both linear and circular configurations [58, 104–106] and are frequently observed in a subset of cancer cell lines, particularly those utilizing the ALT pathway to maintain telomere length without relying on telomerase activity [58,105]. Telomeric (t)-circles, a type of ECTR, are predominantly described as double-stranded circles with nicks or gaps, resulting from the trimming of elongated telomeres [58,105,107] (Fig. 2B). They are observed in various scenarios, including cells experiencing telomere elongation like telomerase+ cancer cell lines [107], and mitogen-stimulated T-lymphocytes [108]. Several factors have been shown to regulate t-circle elaboration in cancer cells, including NBS1, XRCC3, ORC2, and TZAP [106,109–112]. Telomeric (C)- and (G)-circles are distinguished by the presence of intact C-rich and G-rich telomeric DNA, respectively, with partial double-stranded structures [113] (Fig. 2B). Their production is regulated by factors associated with telomere replication stress, with C-circles being more abundant in ALT+ cells. SLX4 and FANCM have been identified as suppressors, while BLM and other members of the BTR complex have been found to promote C-circle formation, in coordination to their impact on ALT-telomere synthesis [54,114–116]. Additionally, MRE11 and RAD51 act as suppressors of C-circle formation in ALT+ cells through a RAD52-independent pathway [117]. The recognition of cytosolic ECTRs by cGAS initiates an innate immune response marked by the production of IFNB1 and defects in cell proliferation [103]. This discovery has prompted the proposal of selectively inducing the cGAS pathway in ALT+ cancer cells with a high abundance of ECTRs as a promising therapeutic approach.

cGAS is activated through direct and high-affinity binding to longer dsDNA fragments (>45 bp), promoting dimerization and facilitating the formation of more stable complexes through a 2:2 DNA/cGAS interaction [118,119]. The formation of phase-separated liquid droplets driven by non-specific interactions results in the coalescence of hundreds of cGAS molecules with immunostimulatory DNA [119,120], enhancing activity and synthesis of the second messenger 2’,3’ cGAMP [92]. The latter binds to STING, located at the endoplasmic reticulum (ER), triggering conformational changes, oligomerization, and translocation of STING to the ER-Golgi intermediate compartment and Golgi apparatus [121,122]. At these sites, STING recruits TBK1 and/or IKKε kinases, along with the transcription factor IRF3, to form a functional signalosome. The STING-TBK1-IRF3 complex signifies the canonical activation of STING signaling, characterized by various regulatory proteins and post-translational modifications on STING, such as Ser 366 phosphorylation and palmitoylation [123]. Once phosphorylated by TBK1, IRF3 undergoes dimerization and translocates into the nucleus, initiating the transcription of IFNB1 that acts through autocrine and paracrine signaling to activate the IFNAR1 and IFNAR2 heterodimeric receptor complex and inducing the transcription of numerous ISGs [124] (Fig. 2D). NF-κB activation, on the other hand, relies on the phosphorylation of its inhibitor IκB by the IκB kinase (IKK) complex. Following phosphorylation, IκB undergoes polyubiquitination and subsequent proteasomal degradation, liberating NF-κB to translocate to the nucleus and regulate downstream proinflammatory cytokines and chemokines [125–127] (Fig. 2D). However, the host has developed mechanisms to regulate the availability of ligands and maintain immunological balance. This is achieved through the degradation activities of DNases, such as extracellular DNases (DNase I and DNase IL3), phagolysosomal DNase (DNase II), and cytosolic DNase (TREX1 or DNase III) [103]. Dysregulation of this pathway can contribute to the development of type I interferonopathies, such as Aicardi-Goutières syndrome (AGS) [128] and systemic lupus erythematosus (SLE) [129], characterized by a chronic activation of cGAS-STING and excessive IFN production.

2.2. Cytosolic RNA-sensing through ZBP1

Telomere-driven innate immunity involves the recognition of cytosolic DNA by the cGAS-STING machinery, as well as the activation of a parallel pathway that relies on sensing Telomeric Repeat-containing RNA (TERRA) transcripts [130–134]. TERRA is synthesized by RNA polymerase II using CpG-rich promoter sequences located in the subtelomeric regions of a majority of human chromosomes, utilizing the C-rich telomeric strand as template [135] (Fig. 2C). Consequently, TERRA molecules consist of chromosome-specific subtelomeric sequences followed by a variable number of telomeric UUAGGG repeats [130,136,137]. The regulation of TERRA promoters involves epigenetic modifications, including DNA methylation mediated by DNMT1 and DNMT3B [137], as well as chromatin alterations facilitated by the homodimerization domain of TRF2 [138]. Depletion of TRF2 or expression of the dominant-negative mutant TRF2ΔBΔM compromises telomere protection and stimulates TERRA synthesis, resembling the altered telomere state observed during an anti-proliferative barrier known as replicative crisis [138–140].

Polyadenylated TERRA transcripts reside in the nucleoplasm, while non-polyadenylated transcripts are found in the nucleoplasm as well as associated with telomeric chromatin [136,141]. The interaction of TERRA with telomeres is facilitated by its telomeric 3’ end, allowing for binding to telomere-associated proteins [142,143] and the formation of RNA:DNA hybrids (R-loops) [114,136,144,145]. Additionally, TERRA molecules have been found in the cytosol [140] and can be secreted within exosome vesicles [146], yet their shuttling dynamics between the nucleus, cytoplasm, and extracellular environment are poorly understood. The biological functions of TERRA at telomeres include regulating telomere replication [147], promoting heterochromatin formation [148], facilitating telomerase recruitment [149–152], and enabling HDR among telomeres in ALT cancer cells [114,142,153–155], while its broader functions at non-telomeric compartments remain mostly elusive.

Our recent understanding of immunostimulatory RNA species has expanded to encompass host-derived RNA ligands and include those transcribed from endogenous EREs, in addition to viral genome and replication intermediates. Upregulation, mislocalization, or misprocessing of these self-RNA species confers them with immunostimulatory properties, potentially contributing to sterile inflammation observed in autoimmune or autoinflammatory disorders [156,157]. TERRA molecules serve as a prime example of this phenomenon. TERRA interacts with the cytosolic NA sensor human ZBP1 (also known as DAI or DLM-1) and triggers innate immune responses and IFN signaling [140]. Originally identified as a cytosolic receptor for DNA [158], ZBP1 has emerged as a versatile sensor capable of detecting Z-form NA, with a particular affinity for RNA molecules [159–166]. This recognition is mediated by its N-terminal Zα1 and Zα2 domains, which can bind to Z-NA in a structure-specific manner, independent of specific sequences or individual base contacts [167–169]. ZBP1 contains two receptor-interacting protein homotypic interaction motif (RHIM) domains. The latter enable interactions with RIPK1 and RIPK3, which are involved in cell death signaling, innate immunity, and inflammation [170,171], as evidenced by studies in mouse models infected with influenza A virus (IAV), vaccinia virus (VACV), and certain herpesviruses [172].

The initial evidence of mouse ZBP1 recognizing viral RNA came from a study with the orthomyxoviruses influenza A and influenza B, which induced RIPK3-dependent cell death [173]. The second Zα domain (Zα2) appears to be responsible for activating cell death signaling as mutations in key Z-NA contact amino acids abolished cell death [160]. During infections with DNA viruses such as murine cytomegalovirus (MCMV) and herpes simplex virus-1, the inhibition of RNA synthesis effectively prevented the activation of ZBP1, suggesting that Z-RNAs, rather than Z-DNAs, are the primary activating ligands [161,162,174]. A recent study revealed that Z-RNAs produced by SARS-CoV-2, potentially from ORF1a and ORF1b genomic regions, activate ZBP1 [175]. It has been proposed that the formation of Z-RNA structures may occur due to torsional stress induced by negative supercoiling during viral replication, similar to what has been observed with dsDNA during cellular transcription [176,177]. Once activated, ZBP1 associates with RIPK3 to execute programmed cell death pathways such as necroptosis, apoptosis, and pyroptosis, depending on the cell type and caspase activity. ZBP1-mediated programmed cell death can even involve the simultaneous activation of these three modes of cell death, leading to the emergence of a cell death pathway termed PANoptosis [178].

In the absence of adenosine deaminase RNA specific 1 (ADAR1) activity, ZBP1 can be activated by EREs derived from mammalian genomes [179–182]. The IFN-inducible p150 isoform of ADAR1, which contains a Zα domain, can bind to Z-NA [183,184], thereby reducing their capacity to activate host RNA sensors. This reduction is achieved in part by introducing adenosine-to-inosine edits in their sequences [185]. Mice lacking ADAR1 p150 expression or carrying a mutation of its Zα domain, exhibit type I IFN-dependent pathology reminiscent of AGS [179–182]. Deletion of ZBP1 mitigates the pathology, reduces the IFN signature, and prolongs animal survival. Despite the technical difficulties in directly evaluating Z-RNA formation in living cells and tissues, the available data indicate that ADAR1 plays a major role in editing RNA transcripts derived from EREs, such as LINE-1 and SINEs, which have a propensity to form Z-RNA structures [181], thereby preventing aberrant activation of ZBP1. The precise mechanism by which ZBP1 triggers pathogenesis in the absence of ADAR1 remains uncertain, as it occurs independently of canonical pathways involving RIPK1, RIPK3, MLKL-mediated necroptosis, and caspase-8-dependent apoptosis, suggesting a novel mode of action [179–182].

Our understanding of ZBP1 signaling mechanisms is largely derived from mouse models, despite the limited similarity in protein sequences between human and murine ZBP1 [186]. The mRNA profiles also differ, with human ZBP1 showing heterogeneity due to alternative splicing and multiple transcription start sites [187]. Many predicted isoforms in humans are not expressed in mouse cells, including the short isoform (ZBP1-S) lacking exon 2, which encodes the first Zα domain [140,187, 188]. ZBP1-S displays distinct subcellular localizations, implying diverse biological functions compared to the full-length protein [168]. In line with this idea, our recent study implicated ZBP1-S in mediating the onset of replicative crisis and preventing the propagation of cells at risk of neoplastic transformation [140]. During crisis, cGAS–STING drives an initial transcriptional induction of ZBP1-S, a prototypical ISG, and primes cells to respond to aberrant accumulation of additional cytosolic immunostimulatory NA species. IFN-induced ZBP1-S is activated by sensing TERRA molecules derived from damaged telomeres, resulting in its redistribution to a distinct subset of mitochondria and the formation of filamentous structures (Fig. 2D). The assembly of ZBP1-S filaments at mitochondria is not dependent on interacting with mitochondrial DNA (mtDNA) or mitochondrial RNA (mtRNA). Disruption of the RHIM1 or Zα2 domains hinders the formation of ZBP1-S filaments and diminishes their involvement in the innate immune response. Interestingly, multimerization, as well as mitochondrial translocation to activate the adaptor protein MAVS [189–192] is shared between ZBP1 and the innate immune RNA sensors RIG-I [193] and MDA-5 [194]. However, these RNA sensors often form aggregated structures rather than filaments, suggesting an alternative oligomerization mechanism for ZBP1 [195].

MAVS, anchored to various subcellular compartments through its C-terminal transmembrane domain, elicits different antiviral signaling responses: The mitochondrial MAVS promotes type I IFN expression, while the peroxisomal MAVS signals for the induction of type III IFN [196–198]. MAVS contains an N-terminal caspase recruitment domain (CARD) that interacts with similar CARD domains present in the RNA sensors RIG-I and MDA5 [199–203]. Upon association with RIG-I and/or MDA5, MAVS forms prion-like polymers on the mitochondrial surface [204,205]. This active state facilitates the recruitment of downstream TRAF effector proteins to create the “MAVS signalosome” [206]. As a result, two molecular cascades become engaged: (a) the phosphorylation of the transcription factors IRF3 and IRF7 by TBK1 and IKKε to induce the expression of type I/III IFNs and (b) the phosphorylation of the transcription factor NF-κB by the IKKα/β/γ complex to upregulate the expression of inflammatory genes [189–191,207] (Fig. 2D).

During crisis, ZBP1-S triggers cell death through a MAVS-mediated IFN response and autophagy, with no evidence of ongoing PANoptosis under these circumstances [140]. Remarkably, cells with compromised ZBP1-MAVS-autophagy pathways gain resistance to cell death and persistently proliferate beyond the crisis barrier, despite their critically short and fused telomeres [140]. These findings firmly establish ZBP1-S signaling as a pivotal component of the crisis program, acting as a tumor suppressive mechanism for eliminating cells with dysfunctional telomeres predisposed to neoplastic transformation (Fig. 2D).

The discovery of a molecular connection between deprotected telomeres, mitochondrial signaling, and innate immune responses underscores a novel interplay among major hallmarks of aging. However, several aspects of this relationship remain poorly understood. One aspect involves the nature of the immunogenic TERRA ligands recognized by ZBP1-S. TERRA, characterized by G-rich repeated sequences, has the ability to form stable hairpins and non-canonical G-quadruplex structures (RG4s) in vitro [208–211] (Fig. 2D). The in vivo formation and functional significance of RG4 structures within TERRA are still uncertain; however, the conformation-specific sensing ability of ZBP1 suggests that RG4s may share similarities with the left-handed Z-RNA structures detected by ZBP1. An alternative possibility is the formation of R-loops resulting from the hybridization of TERRA with the C-rich telomeric strand. These R-loops may undergo processing and excision, leading to their abnormal accumulation in the cytoplasm and subsequent activation of ZBP1-driven innate immunity (Fig. 2C, D). The second unexplored aspect relates to the redistribution of ZBP1 to mitochondria that is essential for activating a MAVS-dependent IFN response. Unlike other RNA sensors that rely on CARD-CARD interactions with MAVS to translocate to mitochondria, ZBP1 lacks a CARD domain. ZBP1 is likely recruited to mitochondria via interactions with proteins at the mitochondria-ER contact sites, which are known to be involved in innate immune signaling [212].

3. Telomere-driven innate immunity and inflammation

Altered immune function and chronic inflammation have long been recognized as substantial contributors to the aging process and its associated diseases [213]. Contrary to previous assumptions [214], recent advancements in genetic studies and clinical observations indicate that the loss of telomere protection as a function of replicative age is not merely a consequence of inflammation but actively fuels the inflammatory process [215,216]. It is therefore essential to reevaluate our understanding of the synergy between telomeres and inflammation, offering valuable insights into the fundamental mechanisms of aging.

3.1. Telomere deprotection and aging

Telomere deprotection, attributed to factors such as the end replication problem, replication slippage, and oxidative damage, imposes replicative barriers that limit the proliferative potential of normal human somatic cells [217–221]. Replicative senescence is triggered upon the recognition of DNA ends as DNA breaks, leading to the activation of DDR pathways, formation of telomere-induced DNA damage foci (TIF), and subsequent cell cycle arrest mediated by the p53/p21^WAF1/CIP1 and p16^INK4A/pRB tumor suppressor pathways [44, 222–224]. Telomere length profiles in senescent cells are heterogeneous and only a few exhibit TIF, suggesting that individual DDR signaling events at telomeres contribute to the onset of senescence. In line with this idea, telomeres in senescence retain a sufficient level of shelterin to partially protect against DNA repair mechanisms while simultaneously triggering DDR signals necessary for an irreversible cell cycle arrest [44, 222,224–227]. In addition to the permanent cessation of cell division, senescence is characterized by morphological and metabolic alterations, resistance to cell death, and the accumulation of cytoplasmic chromatin fragments (CCFs) formed through the extrusion of nuclear chromatin into the cytoplasm due to the loss of nuclear membrane integrity [228]. MN, distinct from CCFs, exhibit a reduced propensity to accumulate in senescent cells. Distinguishing between CCFs and MN microscopically remains challenging, often leading to confusion between the two. While MN-dependent activation of cGAS typically leads to the induction of IFN genes, the activation of cGAS by CCFs in senescent cells is predominantly associated with an NF-κB-dependent cytokine response, contributing to the emergence of the senescence-associated secretory phenotype (SASP) [229–232]. Studies on aged tissues obtained from primate models, including mice, baboons, and humans, have provided evidence of the accumulation of TIF and other markers of replicative senescence during aging [233–240]. Based on these observations, senescent cells are proposed to contribute to tissue aging through two main mechanisms: First, they lose the ability to proliferate and replenish tissues with new cells [241,242]. Second, they secrete molecules that promote tissue dysfunction and inflammation [243], such as degradative enzymes capable of breaking down the extracellular matrix, growth factors, and inflammatory cytokines. Building upon this concept, the targeted elimination of senescent cells or suppressing SASP production using genetic and pharmacological approaches has demonstrated effectiveness in reducing age-related decline and extending the health-span in aged mice [244–246].

Oncogenic events that interfere with the functions of p53 and/or pRB enable cells to proliferate past the senescence barrier until their telomeres reach a critically shortened state, characterized by a near absence of shelterin subunits and activation of DNA repair mechanisms [217, 218,247]. At this stage, a second proliferative barrier known as replicative crisis emerges, marked by a substantial decline in viable cells and increased genome instability often including chromosome fusions, nucleoplasmic bridges (NPBs), MN, and aneuploidy [51,81,248–250]. During crisis, cell death is initiated by the telomere dysfunction-driven accumulation of self-NA species in the cytoplasm, recognized as danger signals that alert the immune system to cope with aberrant cellular activities. Two interconnected cytosolic NA-sensing pathways, namely cGAS-STING activated by cytosolic DNA fragments, and ZBP1-MAVS activated by cytoplasmic TERRA molecules synthesized from damaged telomeres, contribute to the clearance of cells undergoing crisis [140,248]. These pathways synergistically induce a robust type-I IFN responses and sustained inflammatory cascades, leading to the activation of an atypical form of autophagy that facilitates the elimination of cells, rather than promoting viability [140,248]. Autophagy-mediated cell death has been observed in various organisms during developmental [251–254] and pathophysiological [255–258] processes, as well as in cancer cell lines [259], particularly those with impaired apoptosis. While the precise mechanisms underlying the transition of autophagy from a survival pathway to a lethal one are not fully understood, two propositions have emerged: Excessive autophagy flux can lead to the detrimental breakdown of cellular organelles and disrupt cellular homeostasis, or autophagosome membranes can serve as platforms to assemble death-inducing signaling complexes [260].

The accumulation of dicentric chromosomes during crisis, primarily through alt-EJ instead of c-NHEJ [81,261–263], drives complex chromosomal rearrangements and BFB cycles observed in various human tumors, including acute lymphocytic leukemia, squamous cell cancers, and esophageal adenocarcinoma [264,265]. The observations suggest that, during carcinogenesis, replicative crisis occurs prior to the activation of telomere maintenance mechanisms, effectively eliminating pre-malignant cells and serving as a potent barrier against age-related cancer initiation. Further evidence comes from observations of shortened and fused telomeres during the transition from ductal hyperplasia to invasive cancer [266], the initiation of colorectal adenomas [267], and the early stages of chronic lymphocytic leukemia in humans [268]. Studies in mice lacking telomerase and p53 have revealed that telomere dysfunction is associated with the formation of non-reciprocal translocations, focal amplifications, and deletions, mirroring observations made in human cancers [63]. However, the impact of replicative crisis on the aging process, beyond its role in preventing age-related cancer, is not well understood, and the accumulation of crisis cells in aged tissues has not been explored due to the lack of reliable biomarkers, pointing at necessary future research to fill these knowledge gaps.

In addition to the progressive telomere shortening observed during repeated passages in vitro, most human tissues and organs undergo telomere shortening throughout the aging process. Telomere length is negatively associated with age in various cell types such as peripheral blood cells, dermal fibroblasts, intestinal epithelial cells, and mucosal keratinocytes [269–272]. TIF assays, employed to profile telomere deprotection in cells and tissues, have revealed an elevated occurrence of dysfunctional telomeres during aging in various mammalian tissues, including the brain, liver, and skin of baboons [233,234], proliferating and non-proliferating tissues in mice [237–240,273], as well as human skin melanocytes and CD8 + T cells [235,236]. The impact of telomere shortening on organismal aging has been further studied in animal models, particularly in mice and zebrafish, by genetically deleting telomerase component genes either the telomerase RNA component (Terc) or the telomerase reverse transcriptase (TERT) [63,274–276]. Both components function to synthesize telomere repeats on chromosome ends, thereby maintaining telomere length in germline tissues as well as in immortal and cancer cells. Telomerase-deficient zebrafish possess human-like short telomeres that decline with age, disrupting homeostasis in highly proliferative tissues and leading to various degenerative phenotypes and inflammation [275–277]. Late-generation telomerase-knockout mice revealed signs of premature aging, including shortened life expectancy, depletion of tissue stem cell reserves, organ atrophy, and inflammation [274,278–280]. In humans, germline mutations in genes affecting telomerase function or telomere maintenance result in a range of clinical conditions that are collectively termed telomeropathies, short-telomere syndromes, or telomere biology disorders. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely shortened telomeres, often resulting in hematopoietic stem cell failure in the most severe cases, inflammation, premature aging and shortened lifespan [66], highlighting the substantial impact of telomere shortening on overall organismal health and its pivotal role in the aging process.

3.2. Telomere deprotection at the core of inflammaging?

Epidemiological studies have established a connection between inflammation and numerous aging-related diseases, including obesity, type 2 diabetes, cardiovascular diseases, Alzheimer’s disease, and cancer [281]. This led to the concept of inflammaging—a low-grade systemic inflammation that accompanies aging in mammals and links normal aging with age-related diseases sharing an inflammatory foundation [213]. Despite this knowledge, the precise causes of inflammaging remain largely unknown, emphasizing the need for further research to uncover the underlying mechanisms.

The loss of telomere protection contributes to cellular and organismal aging, and disturbances in telomere homeostasis have been associated with several chronic inflammatory conditions. Telomerase-deficient zebrafish show heightened inflammation, increased expression of TNF1-α, and accelerated aging [62]. Late-generation telomerase null mice exhibit both impaired telomeres and age-associated degenerative pathology, including inflammation [63–65]. In the intestinal epithelium, telomere dysfunction results in the activation of the YAP1 transcriptional coactivator and up-regulation of pro-IL-18, a critical immune regulator in the pathogenesis of inflammatory bowel disease [279]. The role of telomere dysfunction as a driver of inflammatory diseases is evident from telomeropathy studies. These disorders arise from germline defects in telomere maintenance genes such as TERT, TERC, PARN, DKC1, NHP2, NOP10, NAF1, WRAP53, as well as mutations affecting the shelterin complex (TIN2, POT1, and TPP1) and telomere replication (CTC1 and RTEL1) [66]. Individuals exhibit impairments in telomere protective mechanisms, experience subclinical manifestations in multiple organs, and develop an increased incidence of idiopathic pulmonary fibrosis, liver cirrhosis, and kidney diseases, all of which relate to increased inflammation [66–68]. Moreover, telomere dysfunction has been recognized as major contributor to a range of inflammatory diseases in older individuals, independent of the presence of genetic polymorphisms in telomere-associated genes [69–72]. In such cases, the presence of dysfunctional telomeres in a subset of cells within affected tissues can trigger localized inflammation, leading to an increased production of reactive oxygen species and further telomere dysfunction in neighboring cells. This exacerbates the inflammatory response and contributes to the development of various age-related conditions like inflammatory bowel disease [282], pancreatitis [283], non-alcoholic fatty liver disease [284], and chronic obstructive pulmonary disease [285]. These findings have established connections between telomere dynamics and age-associated inflammation. However, the debate regarding whether telomere attrition or inflammation is the primary factor remains inconclusive, indicating a likely coexistence and interaction of both components forming a detrimental cycle.

Our recent research suggests that telomere-associated molecular patterns may be the root cause of inflammaging [140] (Fig. 2). In normal cells with functional p53 and pRB pathways, telomere deprotection leads to replicative senescence and the emergence of SASP, characterized by increased secretion of soluble pro-inflammatory cytokines, chemokines, and other inflammatory molecules [286]. The SASP involves a series of poorly understood events that are interconnected with the DDR and NFκB signaling pathways [287,288]. Several groups have identified a consistent pattern of abnormal cGAS-STING activity in different types of senescent cells, including replicative senescence triggered by telomere shortening [231,239]. It has been observed that cGAS is enriched on CCFs that accumulate within senescent cells, contributing to the secretion of specific components of the SASP. In addition to CCFs, other sources of cytosolic DNA species, such as mitochondrial DNA and retrotransposon cDNA, have been observed to accumulate in senescent cells and contribute to the inflammatory SASP [79]. Despite the requirement of the cGAS-STING pathway for both inducing and maintaining the SASP program, its absence has no impact on the activation of ATM-dependent DDR pathway, p53 stabilization, and it does not prevent the onset of replicative senescence in human primary cells [229]. As senescent cells accumulate during aging in both model organisms and humans, the SASP may possess a long-term destructive potential by mediating tissue damage and chronic inflammation [289]. In cells with compromised cell cycle checkpoints, telomere deprotection triggers a distinct cellular program called replicative crisis [140,248,290]. During this phase, dysfunctional telomeres generate cell-intrinsic stimulatory products: Micronuclear DNA activates the cGAS-STING pathway, while cytosolic TERRA RNA molecules interact with the ZBP1-MAVS pathways [140]. These pathways collaborate to induce potent IFN and inflammatory responses, potentially contributing to the increased inflammation observed during the aging process (Fig. 2C). The pro-inflammatory state observed during replicative crisis is fundamentally different from the one associated with senescence, as it predominantly involves IFN signaling and ISGs, which are not actively involved in senescence and therefore not associated with the SASP [291]. To describe the inflammatory secretome produced by crisis cells, we propose the term CASP (Crisis-Associated Secretory Phenotype). The CASP appears to be required for crisis-associated cell death and the onset of this second replicative barrier [140]. Further research will be essential to comprehensively characterize this inflammatory secretome and its implications in cell death during crisis.

As individuals age, systemic chronic inflammation tends to increase, as evidenced by studies showing higher levels of cytokines and chemokines in older individuals [292,293]. Based on our recent research [140, 217,248], we argue that age-related telomere dysfunction is a central driver of inflammaging, with the major source of inflammatory stimuli arising from misplaced self-NA sensed by receptors of the innate immune system cGAS and ZBP1 (Fig. 2). In addition to telomere deprotection, other age-associated alterations can lead to innate immune activation [281]. One particular example is the release of mtDNA into the cytosol, which can be recognized by NLRP3 inflammasome [294], cGAS [295], as well as ZBP1 [296]. The presence of mtDNA circulating in plasma has also been reported during aging and in several specific age-associated diseases [79,297–299]. Although it is not yet known whether circulating cell-free mtDNA is causative in age-associated diseases, given its strong pro-inflammatory potential, it is likely that cytoplasmic and extracellular mtDNA contribute to some extent to chronic inflammation. Modulating innate immune pathways holds significant promise for mitigating chronic inflammation and age-related diseases. However, it is essential to carefully consider potential drawbacks, such as compromising immune surveillance and tumor suppression, and possible side effects on the immune microenvironment.

The study of inflammation and telomere deprotection in relation to aging offers valuable insights. However, their interdependent nature calls for a more synergistic approach to fully grasp the underlying mechanisms of aging and devise effective therapeutic interventions for the elderly. Considering their interconnected roles holds great potential in tackling inflammaging, ultimately leading to improved health and well-being in aging populations.

Abbreviations:

53BP1

Tumor Protein P53 Binding Protein 1

AGS

Aicardi-goutières syndrome

ALT

Alternative lengthening of telomeres

alt-EJ

Alternative end-joining

ATM

Ataxia telangiectasia mutate

ATR

Ataxia telangiectasia and Rad3-related protein

BFB

Breakage-fusion-bridge

BITS

Break-induced telomere synthesis

BLM

Bloom

BRCA1

Breast cancer type 1 susceptibility protein

BRCA2

Breast cancer type 2 susceptibility protein

BTR complex

RecQ helicase BLM, topoisomerase IIIα, and RMI

c-NHEJ

Canonical non-homologous end-joining

CARD

Caspase recruitment domain

CARDIF

CARD adapter inducing interferon beta

CASP

Crisis-associated secretory phenotype

CCFs

Cytoplasmic chromatin fragments

cGAMP

Cyclic guanosine monophosphate–adenosine monophosphate

cGAS

Cyclic GMP-AMP synthase

CTC1

Conserved telomere maintenance component 1

CtIP

CtBP-interacting protein

DAI

DNA-dependent activator of IFN-regulatory factors

DAMPs

Damage-associated molecular patterns

DDR

DNA damage response

DKC

Dyskeratosis congenital

DLM-1

Tumor stroma and activated macrophage protein

DNA-PKcs

DNA-dependent protein kinase catalytic subunit

DNA2

DNA replication ATP-dependent helicase/nuclease DNA2

DNMT1

DNA (cytosine-5)-methyltransferase 1

dsDNA

Double-stranded DNA

ECTR

Extrachromosomal telomere repeat

ER

Endoplasmic reticulum

ERE

Endogenous retroviral elements

ERGIC

ER-Golgi intermediate compartment

EXO1

Exonuclease 1

HDR

Homology-directed repair

IAV

Influenza A virus

iDDR

Inhibitor of DDR

IFN

Interferon

IFNAR1

Interferon alpha/beta receptor 1

IFNAR2

Interferon alpha/beta receptor 2

IFNB1

Interferon beta

IKK

IκB kinase complex

IKK-β

Inhibitor of nuclear factor kappa-B kinase ε

IL

Interleukin

IPS-1

Interferon beta promoter stimulator protein 1

IRF3

Interferon regulatory factor 3

IRF7

Interferon regulatory factor 7

ISG

Interferon-stimulated gene

IκB

Inhibitor of nuclear factor kappa B

Ku

complex Ku70-Ku80

LIG3

Ligase 3

LIG4

Ligase 4

LINE-1

Long interspersed nuclear elements 1

MAM

Mitochondria-associated endoplasmic reticulum membrane

MAPK

Mitogen-activated protein kinase

MAVS

Mitochondrial antiviral signaling protein

MCMV

Murine cytomegalovirus

MDA5

Melanoma differentiation-associated protein 5

MDC1

Mediator of DNA damage checkpoint 1

MLKL

Mixed lineage kinase domain like pseudokinase

MN

Micronuclei

MRN

MRE11, RAD50, and NBS1

NAF1

Nuclear assembly factor 1 ribonucleoprotein

NBS1

Nijmegen breakage syndrome 1

NE

Nuclear envelope

NF-κB

Nuclear factor kappa B

NHP2

Nucleolar protein family A, member 2

NOP10

Nucleolar protein 10

NPB

Nucleoplasmic bridges

OMM

Outer mitochondrial membrane

ORC2

Origin recognition complex subunit 2

ORF

Open reading frame

PALB2

Partner and localizer of BRCA2

PAMPs

Pathogen-associated molecular pattern molecules

PARN

Poly(A)-specific ribonuclease

PARP1

Poly(ADP-Ribose) polymerase 1

PCNA

Proliferating Cell Nuclear Antigen

PNPase

Polyribonucleotide Nucleotidyltransferase 1, Mitochondrial

POT1

Protection of telomeres 1

pRb

RB transcriptional corepressor 1

PRRs

Pattern recognition receptors

RFC1

Replication Factor C Subunit 1

RG4s

RNA G-Quadruplexes

RHIM

RIP homotypic interaction motif

RIG-I

Retinoic Acid-Inducible Gene 1 Protein

RIPK1

Receptor Interacting Serine/Threonine Kinase 1

RIPK3

Receptor Interacting Serine/Threonine Kinase 3

RMI

RecQ-mediated genome instability

RNF168

Ring finger protein 168

RPA

Replication Protein A

RTEL1

Regulator of telomere elongation helicase 1

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

SASP

Senescence-associated secretory phenotype

SINEs

Short interspersed nuclear elements

SLE

Systemic lupus erythematosus

SLX4

Structure-specific endonuclease subunit

SMX complex

SLX1-SLX4, MUS81-EME1, and XPF-ERCC1

ssDNA

Single-stranded DNA

STING

Stimulator of interferon genes protein

SUV3

Suppressor of Var1, 3-Like 1

t-loop

Telomere-loop

T-SCE

Telomere sister chromatid exchange

TBD

Telomere biology disorders

TBK1

TANK binding kinase 1

TCAB1

Telomerase cajal body protein 1

TERC

Telomerase RNA component

TERRA

Telomeric repeat-containing RNA

TERT

Catalytic subunit telomerase reverse transcriptase

TIF

Telomere dysfunction induced foci

TIN2

TERF1 interacting nuclear factor 2

TOP3A

DNA topoisomerase III alpha

TPP1

Tripeptidyl peptidase 1

TRAF

TNF receptor associated factor

TREX1

Three prime repair exonuclease 1

TRF1

Telomeric repeat binding factor 1

TRF2

Telomeric repeat binding factor 2

TZAP

Zinc finger and BTB domain containing 48

VACV

Vaccinia related kinase 2

VISA

Virus-induced signaling adaptor

WRAP53

WD repeat containing antisense to TP53

XRCC3

X-ray repair cross complementing 3

YAP1

Yes1 associated transcriptional regulator

Z-NAs

Z-nucleic acid

ZBP1

Z-DNA binding protein 1

Data Availability

No data was used for the research described in the article.