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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424451/
Aicardi–Goutières Syndrome associated mutations of RNase H2B impair its interaction with ZMYM3 and the CoREST histone-modifying complex
Alexander Shapson-Coe, Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing,¤* Brenda Valeiras, Formal analysis, Methodology, Validation, Christopher Wall, Methodology, Validation, and Cristina Rada, Conceptualization, Formal analysis, Funding acquisition, Investigation, Project administration, Supervision, Writing – original draft, Writing – review & editing*
DNA-RNA hybrids arise in all cell types, and are removed by multiple enzymes, including the trimeric ribonuclease, RNase H2. Mutations in human RNase H2 result in Aicardi–Goutières syndrome (AGS), an inflammatory brain disorder notable for being a Mendelian mimic of congenital viral infection. Previous studies have shown that several AGS-associated mutations of the RNase H2B subunit do not affect trimer stability or catalytic activity and are clustered on the surface of the complex, leading us to speculate that these mutations might impair important interactions of RNase H2 with so far unidentified proteins. In this study, we show that AGS mutations in this cluster impair the interaction of RNase H2 with several members of the CoREST chromatin-silencing complex that include the histone deacetylase HDAC2 and the demethylase KDM1A, the transcriptional regulators RCOR1 and GTFII-I as well as ZMYM3, an MYM-type zinc finger protein. We also show that the interaction is mediated by the zinc finger protein ZMYM3, suggesting that ZMYM3 acts as a novel type of scaffold protein coordinating interactions between deacetylase, demethylase and RNase H type enzymes, raising the question of whether coordination between histone modifications and the degradation of RNA-DNA hybrids may be required to prevent inflammation in humans.
Introduction
Aicardi–Goutières syndrome (AGS) is a rare, largely autosomal-recessive disorder characterised by microcephaly, basal ganglia calcification and elevated levels of lymphocytes and interferon-alpha in the cerebrospinal fluid, with occasional extra-neurological involvement of the liver, spleen and skin [1,2]. AGS usually presents at birth or within the first few months of life, and is strikingly reminiscent of congenital viral infection of the brain, although the failure to find a causative pathogen suggests that AGS may be a disorder of the immune system [2]. The AGS phenotype is thought to result from elevated levels of interferon-alpha, and can be recapitulated by overexpression of interferon-alpha in the murine central nervous system leading to the basal ganglia calcification, angiopathy and astrocytosis seen in AGS patients [3].
Consistent with a central role for interferon in the disease, AGS has been associated with heterozygous gain-of-function mutations in the dsRNA sensor Interferon Induced With Helicase C Domain 1 IFIH1 (MDA5), which increase its affinity for RNA as well as baseline and ligand-induced interferon signalling [4]. AGS has also been associated with homozygous or compound mutations in four nucleases; the DNase TREX1 [5], the dsRNA-specific adenosine deaminase ADAR1 [6], the ribonuclease and deoxynucleoside triphosphohydrolase SAMHD1 [7], and all three subunits of the DNA-RNA hybrid-specific ribonuclease RNase H2 [8]. AGS-associated mutations in any one of these enzymes are thought to result in the accumulation of endogenous nucleic acids, which trigger the expression of interferon-alpha and thereby cause the AGS phenotype. However, while it is clear that accumulation of DNA-RNA hybrids can lead to the activation of the innate immune sensing pathways and interferon production [9], the details of how these interferon-stimulatory endogenous nucleic acids accumulate have not yet been fully established. It is particularly intriguing in the case of deficits in RNase H2 associated with AGS, given the existence of several other RNase activities in the cell capable of the removal of RNA/DNA hybrids.
AGS-associated mutations in RNase H2 may impair its activity on one of two types of DNA-RNA hybrid; DNA-RNA heteroduplexes, including transcription-associated R-Loops [10], and ribonucleotides misincorporated into dsDNA during DNA replication, accumulation of which is associated with the embryonic lethality of RNase H2-null mice [11]. Consistent with this embryonic lethality, no RNase H2-null humans are known to exist, with AGS-associated mutations of the catalytic A subunit reducing but not abolishing catalytic activity in vitro [12]. The structure of human RNase H2 shows that the A, B and C subunits are closely intertwined (Fig 1A), and explains why many of the AGS-associated mutations destabilise the complex [13,14]. Consequently, reduced removal of misincorporated ribonucleotides in RNase H2B heterozygous mutants is associated with systemic autoimmunity [15].
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