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Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy
Open accessAbstract
Hypomorphic mutations in the DNA repair enzyme RNase H2 cause the neuroinflammatory autoimmune disorder Aicardi-Goutières syndrome (AGS). Endogenous nucleic acids are believed to accumulate in patient cells and instigate pathogenic type I interferon expression. However, the underlying nucleic acid species amassing in the absence of RNase H2 has not been established yet. Here, we report that murine RNase H2 knockout cells accumulated cytosolic DNA aggregates virtually indistinguishable from micronuclei. RNase H2-dependent micronuclei were surrounded by nuclear lamina and most of them contained damaged DNA. Importantly, they induced expression of interferon-stimulated genes (ISGs) and co-localized with the nucleic acid sensor cGAS. Moreover, micronuclei associated with RNase H2 deficiency were cleared by autophagy. Consequently, induction of autophagy by pharmacological mTOR inhibition resulted in a significant reduction of cytosolic DNA and the accompanied interferon signature. Autophagy induction might therefore represent a viable therapeutic option for RNase H2-dependent disease. Endogenous retroelements have previously been proposed as a source of self-nucleic acids triggering inappropriate activation of the immune system in AGS. We used human RNase H2-knockout cells generated by CRISPR/Cas9 to investigate the impact of RNase H2 on retroelement propagation. Surprisingly, replication of LINE-1 and Alu elements was blunted in cells lacking RNase H2, establishing RNase H2 as essential host factor for the mobilisation of endogenous retrotransposons.
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“Similarly, cGAS activation due to rupture of the MN nuclear envelope is thought to be the major trigger of an interferon-based inflammatory response (Bartsch et al., 2017; Gekara, 2017; Harding et al., 2017; Mackenzie et al., 2017).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Bartsch et al., 2017
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“For example, the loss of nuclear membrane integrity in senescent cells (Shimi et al., 2011) and laminopathies, such as HGPS, parallels loss of membrane integrity in MN (Bartsch et al., 2017; Gekara, 2017; Harding et al., 2017; Mackenzie et al., 2017).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Bartsch et al., 2017
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“…which then recruit their own nuclear envelope to generate micronuclei. cGAS is recruited to micronuclei upon rupture of their nuclear envelope (Bartsch et The EMBO Journal Carina C de Oliveira Mann & Karl-Peter Hopfner cytosolic compartment and in recruitment and activation of the cytosolic…”
Reece, A. S., & Hulse, G. K. (2020) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000000638 · Cited by 65
“The principal DNA sensor is cGAS (cyclic AMPGMP Synthase) which binds to the signalling scaffold STING (Stimulator of Interferon Genes) which transmits a signal directly to type I interferon genes and signals via the noncanonical pathway to Nuclear Factor kB (NF-kB) which powerfully activates cell-autonomous innate im…”
BackgroundSTING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges
Yang, K., Tang, Z., Xing, C., & Yan, N. (2023) · Neuron · doi:10.1016/j.neuron.2023.10.014 · Cited by 63
Establishing mechanisms affecting the individual response to ionizing radiation
Averbeck, D., Candéias, S. M., Chandna, S., Foray, N., Friedl, A. A., Haghdoost, S., Jeggo, P. A., Lumniczky, K., Paris, F., Quintens, R., et al. (2019) · International Journal of Radiation Biology · doi:10.1080/09553002.2019.1704908 · Cited by 69
“…cyclic GMP-AMP (cGAMP) from ATP and GTP. cGAMP binds to the adaptor Stimulator of Interferon Genes (STING), activating a STAT3-dependent signaling pathway, leading to the transcription of pro-inflammatory type I Interferon (Bartsch et al. 2017; Harding et al. 2017; Mackenzie et al. 2017).”
BackgroundSAMHD1 and the innate immune response to cytosolic DNA during DNA replication
Coquel, F., Neumayer, C., Lin, Y., & Pasero, P. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.09.017 · Cited by 62
Dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP synthase
Abdisalaam, S., Bhattacharya, S., Mukherjee, S., Sinha, D., Kalayarasan, S., Zhu, M., Akbay, E. A., Sadek, H. A., Shay, J. W., & Asaithamby, A. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.012962 · Cited by 58
Causes and consequences of DNA damage-induced autophagy
Juretschke, T., & Beli, P. (2021) · Matrix Biology · doi:10.1016/j.matbio.2021.02.004 · Cited by 59
cGAS–STING signalling in cancer: striking a balance with chromosomal instability
Beernaert, B., & Parkes, E. E. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220838 · Cited by 60
Chen, Y.-H., Chen, H.-H., Wang, W., Chen, H., Huang, W.-S., Kao, C.-H., Lee, S.-R., Yeat, N. Y., Yan, R.-L., Chan, S.-J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38784-z · Cited by 57
Scrambling the genome in cancer: causes and consequences of complex chromosome rearrangements
Krupina, K., Goginashvili, A., & Cleveland, D. W. (2023) · Nature Reviews Genetics · doi:10.1038/s41576-023-00663-0 · Cited by 63
Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition
Choi, J., Hwang, S.-Y., & Ahn, K. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx1312 · Cited by 56
“Although it has been most recently reported that CRISPR/Cas9mediated knockout of RNASEH2A leads to a substantially reduced retrotransposition (34), the role of RNASEH2 in L1 metabolism is thus far not fully proven.”
BackgroundNuclear envelope rupture: little holes, big openings
Hatch, E. M. (2018) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2018.02.001 · Cited by 55
Uehara, R., Cerritelli, S. M., Hasin, N., Sakhuja, K., London, M., Iranzo, J., Chon, H., Grinberg, A., & Crouch, R. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.019 · Cited by 52
“Recent reports demonstrate that defects in RNase H2 result in micronuclei that provide cytoplasmic DNA to stimulate the innate immune response via the cGAS-Sting pathway (Bartsch et al., 2017; Mackenzie et al., 2017).”
BackgroundTREX1 – Apex predator of cytosolic DNA metabolism
Simpson, S. R., Hemphill, W. O., Hudson, T., & Perrino, F. W. (2020) · DNA repair · doi:10.1016/j.dnarep.2020.102894 · Cited by 54
The interplay between autophagy and cGAS-STING signaling and its implications for cancer
Schmid, M., Fischer, P., Engl, M., Widder, J., Gruber, S., & Slade, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1356369 · Cited by 61
Regulation and inhibition of the DNA sensor cGAS
Hertzog, J., & Rehwinkel, J. (2020) · EMBO Reports · doi:10.15252/embr.202051345 · Cited by 52
“…( TREX1 , RNASEH2 genes and SAMHD1 ) leads to type I IFN induction via cGAS (Ablasser et al , 2014; Gao et al , 2015; Gray et al , 2015; Mackenzie et al , 2016; Maelfait et al , 2016; Pokatayev et al , 2016; Bartsch et al , 2017; Mackenzie et al , 2017; Coquel et al , 2018; Xiao et al , 2019).”
Updated roles of cGAS-STING signaling in autoimmune diseases
Liu, Y., & Pu, F. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1254915 · Cited by 50
Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability
Almacellas, E., Pelletier, J., Day, C., Ambrosio, S., Tauler, A., & Mauvezin, C. (2021) · Autophagy · doi:10.1080/15548627.2020.1764727 · Cited by 46
“Although micronuclei are a consequence of chromosome missegregation [62], they can be reabsorbed during subsequent cell divisions or destroyed by autophagy [63,64].”
BackgroundAstrocytes, an active player in Aicardi–Goutières syndrome
Sase, S., Takanohashi, A., Vanderver, A. L., & Almad, A. (2018) · Brain Pathology · doi:10.1111/bpa.12600 · Cited by 45
“These cytoplasmic membrane-bound DNA co-localized with the innate immune sensor cGAS, providing direct evidence for DNA damage mediated activation of cGAS-STING pathway in RNASEH2 mutations (3).”
BackgroundThe triggers of the cGAS-STING pathway and the connection with inflammatory and autoimmune diseases
Zhou, R., Xie, X., Li, X., Qin, Z., Wei, C., Liu, J., & Luo, Y. (2019) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2019.104094 · Cited by 46
Ligands stimulating antitumour immunity as the next G-quadruplex challenge
Miglietta, G., Marinello, J., Russo, M., & Capranico, G. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01649-y · Cited by 44
“The excess of micronuclei in AGS cells also stimulates autophagy, which in turn targets micronuclei for lysosomal degradation, therefore preventing further stimulation of the innate immune response [110].”
BackgroundInfluentialInflammatory signaling in genomically instable cancers
Talens, F., & van Vugt, M. A. T. M. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1638192 · Cited by 43
“Inhibition of autophagy, as a consequence, aggravated the IFN response [50].”
BackgroundInfluentialUnwinding the roles of RNA helicase MOV10
Nawaz, A., Shilikbay, T., Skariah, G., & Ceman, S. (2021) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1682 · Cited by 39
Ribonucleotide Excision Repair Is Essential to Prevent Squamous Cell Carcinoma of the Skin
Hiller, B., Hoppe, A., Haase, C., Hiller, C., Schubert, N., Müller, W., Reijns, M. A. M., Jackson, A. P., Kunkel, T. A., Wenzel, J., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-1099 · Cited by 43
“associated with this damage was shown to occur in RNase H2-deficient cells, leading to formation of micronuclei [24, 25].”
Understanding the birth of rupture-prone and irreparable micronuclei
Guo, X., Dai, X., Wu, X., Zhou, T., Ni, J., Xue, J., & Wang, X. (2020) · Chromosoma · doi:10.1007/s00412-020-00741-w · Cited by 43
Zhu, S., Yan, F., Yang, L., Li, B., Xue, R., Yu, W., Wang, Y., Huang, L., Wang, L., Han, R. Q., et al. (2023) · Theranostics · doi:10.7150/thno.78649 · Cited by 39
Colangelo, N. W., Gerber, N. K., Vatner, R. E., & Cooper, B. T. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1383000 · Cited by 44
“More speci fi cally, it appears autophagy can clear micronuclei (Bartsch et al., 2017) and damaged mitochondria (Lindqvist et al., 2018) before they can release dsDNA into the cytosol.”
BackgroundMechanistic link between DNA damage sensing, repairing and signaling factors and immune signaling
Mukherjee, S., Abdisalaam, S., Bhattacharya, S., Kalayarasan, S., Sinha, D., & Asaithamby, A. (2019) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2018.11.004 · Cited by 39
“Recent findings have provided mechanistic insights into how the accumulation of chromatin fragments in the form of micronuclei and the subsequent rupture of the nuclear envelope initiate the cGAS-STING-mediated cytosolic DNA sensing pathway (Bartsch et al., 2017; Dou et al., 2017; Gluck et al., 2017; Harding et al., 2…”
BackgroundActivating the Nucleic Acid-Sensing Machinery for Anticancer Immunity
Medler, T. R., Patel, J. M., Alice, A. F., Baird, J. R., Hu, H., & Gough, M. J. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.08.006 · Cited by 36
Double-checking chromosome segregation
Maiato, H., & Silva, S. D. R. (2023) · The Journal of Cell Biology · doi:10.1083/jcb.202301106 · Cited by 37
“, 2018), lysosome-mediated autophagy (Bartsch et al., 2017; Rello-Varona et al., 2012; Zhao et al., 2021), or extrusion through the cytoplasmic membrane (Schriever-Schwemmer et al.”
BackgroundDuardo, R. C., Marinello, J., Russo, M. V., Morelli, S., Pepe, S., Guerra, F., Gómez‐González, B., Aguilera, A., & Capranico, G. (2024) · Science Advances · doi:10.1126/sciadv.adm8196 · Cited by 35
“In addition, mutations of ribonucle-ase (RNase) H2, an endonuclease specifically targeting RNA strands of hybrid duplexes, can cause the human Aicardi-Goutières syndrome and an increase in micronuclei triggering a persistent inflammatory activation, likely at the basis of the syndrome ( 35 – 37 ).”
Activation and regulation of cGAS-STING signaling in cancer cells
Shim, A., Chen, Y., & Maciejowski, J. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.08.030 · Cited by 37
The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders
Matz, K. M., Guzman, R. M., & Goodman, A. G. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.08.002 · Cited by 32
Metadata
- Authors
- Bartsch, K., Knittler, K., Borowski, C., Rudnik, S., Damme, M., Aden, K., Spehlmann, M. E., Frey, N., Saftig, P., Chalaris, A., & Rabe, B.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- University Hospital Schleswig-Holstein (DE)
- Corresponding author
- Rabe, Björn
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-07-17
- Volume
- 26
- Issue
- 20
- Pages
- 3960-3972
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2735349030
- Cited by
- 196
- References
- 52
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 18 · 2023: 23 · 2022: 20 · 2021: 27 · 2020: 25 · 2019: 28 · 2018: 31 · 2017: 2
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (RA 2404/1-1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- RNase H2, Aicardi-Goutières syndrome, autophagy, micronuclei, cytosolic DNA, type I interferon, cGAS, interferon-stimulated genes, endogenous retrotransposons, LINE-1, Alu elements, mTOR inhibition, DNA repair, neuroinflammation
- MeSH terms
- Animals, Autophagy, DNA, DNA Damage, DNA Replication, Mutation, Nervous System Malformations, Ribonuclease H, Mice, Knockout, Autoimmune Diseases of the Nervous System, Micronucleus, Germline, Mice
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