The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death

Zierhut, Christian; Yamaguchi, Norihiro; Paredes, Maria Cristina Garcia; Luo, Ji‐Dung; Carroll, Thomas; Funabiki, Hironori

doi:10.1016/j.cell.2019.05.035

Cited by 301 publications

(301 citation statements)

References 87 publications

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“…cGAS is generally considered as a cytosolic protein but transiently accumulates in the nucleus following mitotic nuclear membrane dissolution (Yang et al, 2017;Gentili et al, 2019;Zierhut et al, 2019). Moreover, cGAS has also been reported to actively translocate from the cytosol into the nucleus upon DNA damage (Liu et al, 2018) but also localizes to the plasma membrane in some cell types (Barnett et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

et al. 2019

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DNA repair via homologous recombination (HR) is indispensable for genome integrity and cell survival but if unrestrained can result in undesired chromosomal rearrangements. The regulatory mechanisms of HR are not fully understood. Cyclic GMP‐AMP synthase (cGAS) is best known as a cytosolic innate immune sensor critical for the outcome of infections, inflammatory diseases, and cancer. Here, we report that cGAS is primarily a chromatin‐bound protein that inhibits DNA repair by HR, thereby accelerating genome destabilization, micronucleus generation, and cell death under conditions of genomic stress. This function is independent of the canonical STING‐dependent innate immune activation and is physiologically relevant for irradiation‐induced depletion of bone marrow cells in mice. Mechanistically, we demonstrate that inhibition of HR repair by cGAS is linked to its ability to self‐oligomerize, causing compaction of bound template dsDNA into a higher‐ordered state less amenable to strand invasion by RAD51‐coated ssDNA filaments. This previously unknown role of cGAS has implications for understanding its involvement in genome instability‐associated disorders including cancer.

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Section: Introductionmentioning

confidence: 99%

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

et al. 2019

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“…Recent work has shown that upon NEBD, cGAS localizes to mitotic chromosomes via direct binding to H2a/H2b dimers [53]. However this binding is not via the DNA-binding domains of cGAS that underlie DNAdependent activation, resulting in a relatively low production of cGAMP.…”

Section: Cgas and Sting Are Non-responsive During Mitosismentioning

confidence: 99%

“…However this binding is not via the DNA-binding domains of cGAS that underlie DNAdependent activation, resulting in a relatively low production of cGAMP. Thus, chromatin appears to blunt cGAS activation [34,53], suggesting a means for the cell to avoid cGAS-driven IFN responses to self chromosomes during open mitosis. One unexplored aspect is whether chromatin-bound cGAS, or the pool of cGAS that might remain cytosolic during open mitosis, would still be responsive to foreign (naked) DNA-and whether that activation would then cause IRF3 phosphorylation.…”

Section: Cgas and Sting Are Non-responsive During Mitosismentioning

confidence: 99%

“…Since cGAS localizes to condensed chromosomes upon NEBD [35,53], others have asked whether cGAS is activated by chromosomes, and if not, what mechanisms exist to prevent such selfactivation. Recent studies have revealed that i) chromosome-bound cGAS is tightly tethered to chromatin, potentially via interactions with H2a/H2b dimers, ii) chromatin interaction does not involve the DNA-binding domains of cGAS required for "typical" activation by dsDNA, and iii) that chromosome binding results only in weak activation of cGAS with relatively low production of cGAMP [34,53,54].…”

Section: Introductionmentioning

confidence: 99%

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Attenuation of cGAS/STING Activity During Mitosis

Uhlorn

Gamez

et al. 2019

Preprint

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The innate immune system recognizes cytosolic DNA associated with microbial infections or cellular stress via the cGAS/STING pathway, leading to activation of phospho-IRF3 and downstream IFN-I and senescence responses. To prevent hyperactivation, cGAS/STING is presumed to be non-responsive to chromosomal self DNA during open mitosis, though specific regulatory mechanisms are lacking. Given a role for the Golgi in STING activation, we investigated the state of the cGAS/STING pathway in interphase cells with artificially vesiculated Golgi and in cells arrested in mitosis. We find that while cGAS activity is impaired through interaction with mitotic chromosomes, Golgi integrity has little effect on the enzyme's production of cGAMP. In contrast, STING activation in response to either foreign DNA (cGAS-dependent) or exogenous cGAMP is impaired by a vesiculated Golgi. Overall our data suggest a secondary means for cells to limit potentially harmful cGAS/STING responses during open mitosis via natural Golgi vesiculation.

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“…The latter may ultimately lead to the activation of death receptor signaling. Yet, one recent report on bioRxiv actually provides evidence that upon extended mitotic arrest, cGAS can be detected along mitotic chromosomes and that blocking cGAS/STING signaling delays mitotic death upon taxol treatment when slippage is blocked by APC/C inhibition [preprint: ]. Intriguingly, cell death appears to involve a non‐transcriptional activity of IRF3 that has previously been reported in the context of infection with dsRNA viruses, that is, to be able to directly activate BAX via protein–protein interaction at the mitochondrial outer membrane .…”

Section: Introductionmentioning

confidence: 99%

Perturbing mitosis for anti‐cancer therapy: is cell death the only answer?

et al. 2018

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Interfering with mitosis for cancer treatment is an old concept that has proven highly successful in the clinics. Microtubule poisons are used to treat patients with different types of blood or solid cancer since more than 20 years, but how these drugs achieve clinical response is still unclear. Arresting cells in mitosis can promote their demise, at least in a petri dish. Yet, at the molecular level, this type of cell death is poorly defined and cancer cells often find ways to escape. The signaling pathways activated can lead to mitotic slippage, cell death, or senescence. Therefore, any attempt to unravel the mechanistic action of microtubule poisons will have to investigate aspects of cell cycle control, cell death initiation in mitosis and after slippage, at single‐cell resolution. Here, we discuss possible mechanisms and signaling pathways controlling cell death in mitosis or after escape from mitotic arrest, as well as secondary consequences of mitotic errors, particularly sterile inflammation, and finally address the question how clinical efficacy of anti‐mitotic drugs may come about and could be improved.

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The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death

Cited by 301 publications

References 87 publications

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

Attenuation of cGAS/STING Activity During Mitosis

Perturbing mitosis for anti‐cancer therapy: is cell death the only answer?

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