Journal of Molecular Medicine

, Volume 91, Issue 11, pp 1235–1240 | Cite as

Aicardi–Goutières syndrome: clues from the RNase H2 knock-out mouse

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Abstract

Ribonuclease H2 (RNase H2) belongs to the family of RNase H enzymes, which process RNA/DNA hybrids. Apart from cleaving the RNA moiety of a plain RNA/DNA hybrid, RNase H2 participates in the removal of single ribonucleotides embedded in a DNA duplex. Mutations in RNase H2 lead to the chronic inflammatory disorder Aicardi–Goutières syndrome (AGS), which has significant phenotypic overlaps with the autoimmune disease systemic lupus erythematosus. RNase H2 knock-out mice are embryonic lethal. Mouse embryos lacking RNase H2 accumulate DNA damage and exhibit a p53-mediated growth arrest commencing at gastrulation. On a molecular level, the knock-out mice reveal that RNase H2 represents an essential DNA repair enzyme, whose main cellular function is the removal of accidentally misincorporated ribonucleotides from genomic DNA. Ribonucleotides strongly accumulate within the genomic DNA of RNase H2-deficient cells, in turn resulting in a massive build-up of DNA damage in these cells. The DNA lesions that arise from misincorporated ribonucleotides constitute the by far most frequent type of naturally occurring DNA damage. AGS-causing mutations have also been found in the genes of the 3′-exonuclease TREX1, the dNTP triphosphatase SAMHD1, as well as the RNA-editing enzyme ADAR1, defining defects in nucleic acid metabolism pathways as a common hallmark of AGS pathology. However, recent evidence gathered from RNase H2 knock-out mice might provide additional insight into the molecular mechanisms underlying AGS development and a potential role of DNA damage as a trigger of autoimmunity is discussed.

Keywords

RNase H2 Aicardi–Goutières syndrome Autoimmunity Interferon α 
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References

  1. 1.
    Rice G, Patrick T, Parmar R, Taylor CF, Aeby A, Aicardi J, Artuch R, Montalto SA, Bacino CA, Barroso B et al (2007) Clinical and molecular phenotype of Aicardi–Goutières syndrome. Am J Hum Genet 81:713–725PubMedCrossRefGoogle Scholar
  2. 2.
    McEntagart M, Kamel H, Lebon P, King MD (1998) Aicardi–Goutières syndrome: an expanding phenotype. Neuropediatrics 29:163–167PubMedCrossRefGoogle Scholar
  3. 3.
    Aicardi J, Goutieres F (1984) A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 15:49–54PubMedCrossRefGoogle Scholar
  4. 4.
    Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA et al (2009) Mutations involved in Aicardi–Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet 41:829–832PubMedCrossRefGoogle Scholar
  5. 5.
    Xin B, Jones S, Puffenberger EG, Hinze C, Bright A, Tan H, Zhou A, Wu G, Vargus-Adams J, Agamanolis D et al (2011) Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke. Proc Natl Acad Sci U S A 108:5372–5377PubMedCrossRefGoogle Scholar
  6. 6.
    Crow YJ, Rehwinkel J (2009) Aicardi–Goutières syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum Mol Genet 18:R130–R136PubMedCrossRefGoogle Scholar
  7. 7.
    Rigby RE, Leitch A, Jackson AP (2008) Nucleic acid-mediated inflammatory diseases. Bioessays 30:833–842PubMedCrossRefGoogle Scholar
  8. 8.
    Crow Y, Hayward B, Parmar R, Robins P, Leitch A, Ali M, Black D, van Bokhoven H, Brunner H, Hamel B et al (2006) Mutations in the gene encoding the 3–5′ DNA exonuclease TREX1 cause Aicardi–Goutières syndrome at the AGS1 locus. Nat Genet 38:917–920PubMedCrossRefGoogle Scholar
  9. 9.
    Crow Y, Leitch A, Hayward B, Garner A, Parmar R, Griffith E, Ali M, Semple C, Aicardi J, Babul-Hirji R et al (2006) Mutations in genes encoding ribonuclease H2 subunits cause Aicardi–Goutières syndrome and mimic congenital viral brain infection. Nat Genet 38:910–916PubMedCrossRefGoogle Scholar
  10. 10.
    Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, Dickerson JE, Bhaskar SS, Zampini M, Briggs TA et al (2012) Mutations in ADAR1 cause Aicardi–Goutières syndrome associated with a type I interferon signature. Nat Genet 44:1243–1248PubMedCrossRefGoogle Scholar
  11. 11.
    Stetson DB, Medzhitov R (2006) Type I interferons in host defense. Immunity 25:373–381PubMedCrossRefGoogle Scholar
  12. 12.
    Goutieres F, Aicardi J, Barth PG, Lebon P (1998) Aicardi–Goutières syndrome: an update and results of interferon-alpha studies. AnnNeurol 44:900–907Google Scholar
  13. 13.
    Van Heteren JT, Rozenberg F, Aronica E, Troost D, Lebon P, Kuijpers TW (2008) Astrocytes produce interferon-alpha and CXCL10, but not IL-6 or CXCL8, in Aicardi–Goutières syndrome. Glia 56:568–578PubMedCrossRefGoogle Scholar
  14. 14.
    Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100:2610–2615PubMedCrossRefGoogle Scholar
  15. 15.
    Liu Z, Davidson A (2012) Taming lupus—a new understanding of pathogenesis is leading to clinical advances. Nat Med 18:871–882PubMedCrossRefGoogle Scholar
  16. 16.
    Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M (2010) The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol 6:280–289PubMedCrossRefGoogle Scholar
  17. 17.
    Ramantani G, Kohlhase J, Hertzberg C, Innes AM, Engel K, Hunger S, Borozdin W, Mah JK, Ungerath K, Walkenhorst H et al (2010) Expanding the phenotypic spectrum of lupus erythematosus in Aicardi–Goutières syndrome. Arthritis Rheum 62:1469–1477PubMedCrossRefGoogle Scholar
  18. 18.
    Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, Robins P, Harvey S, Hollis T, O'Hara A et al (2007) Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi–Goutières syndrome. Am J Hum Genet 80:811–815PubMedCrossRefGoogle Scholar
  19. 19.
    Lee-Kirsch MA, Chowdhury D, Harvey S, Gong M, Senenko L, Engel K, Pfeiffer C, Hollis T, Gahr M, Perrino FW et al (2007) A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med 85:531–537PubMedCrossRefGoogle Scholar
  20. 20.
    Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, Crow YJ (2011) Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A 155A:235–237PubMedCrossRefGoogle Scholar
  21. 21.
    Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, de Silva U, Bailey SL, Witte T, Vyse TJ et al (2007) Mutations in the gene encoding the 3–5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 39:1065–1067PubMedCrossRefGoogle Scholar
  22. 22.
    Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO, Adler A, Alarcon-Riquelme ME, Gallant CJ, Boackle SA, Criswell LA et al (2011) Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 12(4):270–279. doi: 10.1038/gene.2010.73, Epub 2011 Jan 27PubMedCrossRefGoogle Scholar
  23. 23.
    Campbell IL, Krucker T, Steffensen S, Akwa Y, Powell HC, Lane T, Carr DJ, Gold LH, Henriksen SJ, Siggins GR (1999) Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha. Brain Res 835:46–61PubMedCrossRefGoogle Scholar
  24. 24.
    Gall A, Treuting P, Elkon KB, Loo YM, Gale M Jr, Barber GN, Stetson DB (2012) Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36:120–131PubMedCrossRefGoogle Scholar
  25. 25.
    Izzotti A, Pulliero A, Orcesi S, Cartiglia C, Longobardi MG, Capra V, Lebon P, Cama A, La Piana R, Lanzi G et al (2009) Interferon-related transcriptome alterations in the cerebrospinal fluid cells of Aicardi–Goutières patients. Brain Pathol 19:650–660PubMedCrossRefGoogle Scholar
  26. 26.
    Cuadrado E, Jansen MH, Anink J, De Filippis L, Vescovi AL, Watts C, Aronica E, Hol EM, Kuijpers TW (2013) Chronic exposure of astrocytes to interferon-alpha reveals molecular changes related to Aicardi–Goutières syndrome. Brain 136:245–258PubMedCrossRefGoogle Scholar
  27. 27.
    Morita M, Stamp G, Robins P, Dulic A, Rosewell I, Hrivnak G, Daly G, Lindahl T, Barnes DE (2004) Gene-targeted mice lacking the Trex1 (DNase III) 3′-->5′ DNA exonuclease develop inflammatory myocarditis. Mol Cell Biol 24:6719–6727PubMedCrossRefGoogle Scholar
  28. 28.
    Stetson DB, Ko JS, Heidmann T, Medzhitov R (2008) Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587–598PubMedCrossRefGoogle Scholar
  29. 29.
    Crow YJ (2011) Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 1238:91–98PubMedCrossRefGoogle Scholar
  30. 30.
    Reijns MA, Rabe B, Rigby RE, Mill P, Astell KR, Lettice LA, Boyle S, Leitch A, Keighren M, Kilanowski F et al (2012) Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 149:1008–1022PubMedCrossRefGoogle Scholar
  31. 31.
    Shaban NM, Harvey S, Perrino FW, Hollis T (2010) The structure of the mammalian RNase H2 complex provides insight into RNA. NA hybrid processing to prevent immune dysfunction. J Biol Chem 285:3617–3624PubMedCrossRefGoogle Scholar
  32. 32.
    Reijns MA, Bubeck D, Gibson LC, Graham SC, Baillie GS, Jones EY, Jackson AP (2011) The structure of the human RNase H2 complex defines key interaction interfaces relevant to enzyme function and human disease. J Biol Chem 286:10530–10539PubMedCrossRefGoogle Scholar
  33. 33.
    Bubeck D, Reijns MA, Graham SC, Astell KR, Jones EY, Jackson AP (2011) PCNA directs type 2 RNase H activity on DNA replication and repair substrates. Nucleic Acids Res 39:3652–3666PubMedCrossRefGoogle Scholar
  34. 34.
    Cerritelli SM, Crouch RJ (2009) Ribonuclease H: the enzymes in eukaryotes. FEBS J 276:1494–1505PubMedCrossRefGoogle Scholar
  35. 35.
    Hiller B, Achleitner M, Glage S, Naumann R, Behrendt R, Roers A (2012) Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. J Exp Med 209:1419–1426PubMedCrossRefGoogle Scholar
  36. 36.
    Stein H, Hausen P (1969) Enzyme from calf thymus degrading the RNA moiety of DNA–RNA hybrids: effect on DNA-dependent RNA polymerase. Science 166:393–395PubMedCrossRefGoogle Scholar
  37. 37.
    Machida Y, Okazaki T, Okazaki R (1977) Discontinuous replication of replicative form DNA from bacteriophage phiX174. Proc Natl Acad Sci U S A 74:2776–2779PubMedCrossRefGoogle Scholar
  38. 38.
    Huertas P, Aguilera A (2003) Cotranscriptionally formed DNA: RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol Cell 12:711–721PubMedCrossRefGoogle Scholar
  39. 39.
    Bhoj VG, Chen ZJ (2008) Linking retroelements to autoimmunity. Cell 134:569–571PubMedCrossRefGoogle Scholar
  40. 40.
    Nick McElhinny SA, Kumar D, Clark AB, Watt DL, Watts BE, Lundstrom EB, Johansson E, Chabes A, Kunkel TA (2010) Genome instability due to ribonucleotide incorporation into DNA. Nat Chem Biol 6:774–781PubMedCrossRefGoogle Scholar
  41. 41.
    Kim N, Huang SN, Williams JS, Li YC, Clark AB, Cho JE, Kunkel TA, Pommier Y, Jinks-Robertson S (2011) Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I. Science 332:1561–1564PubMedCrossRefGoogle Scholar
  42. 42.
    Brzostek-Racine S, Gordon C, Van Scoy S, Reich NC (2011) The DNA damage response induces IFN. J Immunol 187:5336–5345PubMedCrossRefGoogle Scholar
  43. 43.
    Yang Y, Lindahl T, Barnes D (2007) Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–886PubMedCrossRefGoogle Scholar
  44. 44.
    Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J (2010) The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol 11:1005–1013PubMedCrossRefGoogle Scholar
  45. 45.
    Yan N, Lieberman J (2011) Gaining a foothold: how HIV avoids innate immune recognition. Curr Opin Immunol 23:21–28PubMedCrossRefGoogle Scholar
  46. 46.
    Beck-Engeser GB, Eilat D, Wabl M (2011) An autoimmune disease prevented by anti-retroviral drugs. Retrovirology 8:91PubMedCrossRefGoogle Scholar
  47. 47.
    Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, Florens L, Washburn MP, Skowronski J (2011) Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474:658–661PubMedCrossRefGoogle Scholar
  48. 48.
    Baldauf HM, Pan X, Erikson E, Schmidt S, Daddacha W, Burggraf M, Schenkova K, Ambiel I, Wabnitz G, Gramberg T et al (2012) SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat Med 18:1682–1687PubMedCrossRefGoogle Scholar
  49. 49.
    Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HC, Rice GI, Christodoulou E, Walker PA, Kelly G, Haire LF, Yap MW et al (2011) HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480:379–382PubMedCrossRefGoogle Scholar
  50. 50.
    Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, Bloch N, Maudet C, Bertrand M, Gramberg T et al (2012) SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol 13:223–228PubMedCrossRefGoogle Scholar
  51. 51.
    Genovesio A, Kwon YJ, Windisch MP, Kim NY, Choi SY, Kim HC, Jung S, Mammano F, Perrin V, Boese AS et al (2011) Automated genome-wide visual profiling of cellular proteins involved in HIV infection. J Biomol Screen 16:945–958PubMedCrossRefGoogle Scholar
  52. 52.
    Kennedy EM, Amie SM, Bambara RA, Kim B (2012) Frequent incorporation of ribonucleotides during HIV-1 reverse transcription and their attenuated repair in macrophages. J Biol Chem 287:14280–14288PubMedCrossRefGoogle Scholar
  53. 53.
    Goodier JL, Kazazian HH Jr (2008) Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135:23–35PubMedCrossRefGoogle Scholar
  54. 54.
    Chiu YL, Greene WC (2008) The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu Rev Immunol 26:317–353PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Institute of BiochemistryChristian Albrechts UniversityKielGermany

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