The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
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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Genome engineering using the CRISPR-Cas9 system
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Trex1 prevents cell-intrinsic initiation of autoimmunity
Stetson, D. B., Ko, J. S., Heidmann, T., & Medzhitov, R. (2008) · Cell · doi:10.1016/j.cell.2008.06.032 · Cited by 1,280
LINE-mediated retrotransposition of marked Alu sequences
Dewannieux, M., Esnault, C., & Heidmann, T. (2003) · Nature Genetics · doi:10.1038/ng1223 · Cited by 1,026
Aicardi–Goutières syndrome and the type I interferonopathies
Crow, Y. J., & Manel, N. (2015) · Nature Reviews Immunology · doi:10.1038/nri3850 · Cited by 925
Ribonuclease H: the enzymes in eukaryotes
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Levine, B., & Kroemer, G. (2019) · Cell · doi:10.1016/j.cell.2018.09.048 · Cited by 2,832
The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer
Li, T., & Chen, Z. J. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180139 · Cited by 1,293
“A consequence of micronuclei rupture is that chromosomal DNA become accessible to cGAS (Bartsch et al., 2017; Dou et al., 2017; Glück et al., 2017; Harding et al., 2017; Mackenzie et al., 2017; Yang et al., 2017).”
BackgroundInflammatory microenvironment remodelling by tumour cells after radiotherapy
McLaughlin, M., Patin, E. C., Pedersen, M., Wilkins, A. C., Dillon, M. T., Melcher, A. A., & Harrington, K. J. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0246-1 · Cited by 921
Targeting immunogenic cell stress and death for cancer therapy
Galluzzi, L., Guilbaud, E., Schmidt, D. R., Kroemer, G., & Marincola, F. M. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-00920-9 · Cited by 638
“150,151); by autophagy-dependent degradation of cellular sources of cGAS-activatory DNA species, including permeabilized mitochondria 152 and micronuclei 153,154 ; and through defects in the signal transducers of type I interferon receptors, such as Janus kinase 1 (JAK1) 155 .”
Linking cellular stress responses to systemic homeostasis
Galluzzi, L., Yamazaki, T., & Kroemer, G. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0068-0 · Cited by 556
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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