ER-Directed TREX1 Limits cGAS Recognition of Micronuclei

Mohr, Lisa; Toufektchan, Eléonore; Chu, Kevan; Maciejowski, John

doi:10.2139/ssrn.3606800

Cited by 7 publications

(13 citation statements)

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“…1d ) 15 . Additionally, DNA bridges were not found to elicit significant cGAS/STING signaling in an analogous model of telomere crisis in cGAS-positive MCF10A cells 16 . Nonetheless, we cannot fully rule out a difference in the survival of the TREX1 KO clones that may affect the frequency of observed rearrangements.…”

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confidence: 87%

APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis

et al. 2020

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Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes 1 – 5 . Here we examine the mechanism underlying chromothripsis and kataegis using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes 4 , plays a prominent role in chromothriptic fragmentation. In absence of TREX1, the genome alterations induced by telomere crisis primarily involve Breakage-Fusion-Bridge cycles and simple genome rearrangements rather than chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.

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confidence: 87%

APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis

et al. 2020

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“…An inflammatory signaling cascade is thus a possible downstream consequence of unresolved DNA damage, but negative regulators will balance this response. For example, the TREX1 3′ exonuclease may localize to ruptured micronuclei, degrading the exposed dsDNA and obviating recognition by cGAS [ 45 ]. Some micronuclei are removed from the cytosol by autophagy, similarly preventing PRR nucleation [ 46 ].…”

Section: Micronuclei Are a Reservoir Of Immunostimulatory Nucleic Acimentioning

confidence: 99%

“…However, given that apoptosis is generally considered an immunologically silent event (reviewed by [ 63 ]), the influence of mtDNA on DDR-mediated inflammatory programs may not directly follow from intrinsic apoptotic signaling. Primary nuclear envelope rupture, for example via chromatin bridge breakage, is yet another mechanism whereby dsDNA can become exposed to the cytosol [ 3 , 4 , 45 ]. DSBs can accumulate in the primary nucleus if these ruptures are not immediately repaired, which primes micronuclei formation in subsequent mitoses [ 64 ].…”

Section: Other Sources Of Immunostimulatory Nucleic Acidsmentioning

confidence: 99%

Alerting the immune system to DNA damage: micronuclei as mediators

MacDonald

Benguerfi

Harding

2020

Essays in Biochemistry

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Healthy cells experience thousands of DNA lesions per day during normal cellular metabolism, and ionizing radiation and chemotherapeutic drugs rely on DNA damage to kill cancer cells. In response to such lesions, the DNA damage response (DDR) activates cell-cycle checkpoints, initiates DNA repair mechanisms, or promotes the clearance of irreparable cells. Work over the past decade has revealed broader influences of the DDR, involving inflammatory gene expression following unresolved DNA damage, and immune surveillance of damaged or mutated cells. Subcellular structures called micronuclei, containing broken fragments of DNA or whole chromosomes that have been isolated away from the rest of the genome, are now recognized as one mediator of DDR-associated immune recognition. Micronuclei can initiate pro-inflammatory signaling cascades, or massively degrade to invoke distinct forms of genomic instability. In this mini-review, we aim to provide an overview of the current evidence linking the DDR to activation of the immune response through micronuclei formation, identifying key areas of interest, open questions, and emerging implications.

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“…69,70 In addition, cytoplasmic exonuclease TREX1 tends to accumulate to 40-70% of ruptured micronuclei and contributes to the de novo generation of ssDNA in micronuclei. 71 Ruptured mNE will fuse with lysosomes, which lead to increased DNA damage in micronucleus, 49 probably due to the nucleases 72 or acidic environments in lysosomes. Besides, cytoplasm also contains the structure-selective endonucleases involved in degrading intermediates generated during HR and replication stress.…”

Section: Micronuclei Prefer For Rapid Mutagenesismentioning

confidence: 99%

“…This binding not only activates the innate immunity by initiating the STING‐IRF3‐type I interferon signaling cascade (reviewed in 5 ), but also has potent impacts on DNA repair in micronucleus because cGAS is an inhibitor of HR‐based DNA repair 69,70 . In addition, cytoplasmic exonuclease TREX1 tends to accumulate to 40‐70% of ruptured micronuclei and contributes to the de novo generation of ssDNA in micronuclei 71 . Ruptured mNE will fuse with lysosomes, which lead to increased DNA damage in micronucleus, 49 probably due to the nucleases 72 or acidic environments in lysosomes.…”

Section: Micronuclei Prefer For Rapid Mutagenesismentioning

confidence: 99%

Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

Guo

Dai

et al. 2020

Intl Journal of Cancer

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Micronuclei, small spatially-separated, nucleus-like structures, are a common feature of human cancer cells. There are considerable heterogeneities in the sources, structures and genetic activities of micronuclei. Accumulating evidence suggests that micronuclei and main nuclei represent separate entities with respect to DNA replication, DNA damage sensing and repairing capacity because micronuclei are not monitored by the same checkpoints nor covered by the same nuclear envelope as the main nuclei. Thus, micronuclei are spatially restricted "mutation factories." Several large-scale DNA sequencing and bioinformatics studies over the last few years have revealed that most micronuclei display a mutational signature of chromothripsis immediately after their generation and the underlying molecular mechanisms have been dissected extensively. Clonal expansion of the micronucleated cells is contextdependent and is associated with chromothripsis and several other mutational signatures including extrachromosomal circular DNA, kataegis and chromoanasynthesis. These results suggest what was once thought to be merely a passive indicator of chromosomal instability is now being recognized as a strong mutator phenotype that may drive intratumoral genetic heterogeneity. Herein, we revisit the actionable determinants that contribute to the bursts of mutagenesis in micronuclei and present the growing number of evidence which suggests that micronuclei have distinct shortand long-term mutational and functional effects to cancer genomes. We also pose challenges for studying the long-term effects of micronucleation in the upcoming years.

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ER-Directed TREX1 Limits cGAS Recognition of Micronuclei

Cited by 7 publications

References 0 publications

APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis

APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis

Alerting the immune system to DNA damage: micronuclei as mediators

Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

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