TREX1 DNA exonuclease deficiency, accumulation of single stranded DNA and complex human genetic disorders

Article English OPEN
O'Driscoll, Mark (2008)

Aicardi-Goutieres syndrome (AGS) is an unusual condition that clinically mimics a congenital viral infection. Several genes have recently been implicated in the aetiology of this disorder. One of these genes encodes the DNA exonuclease TREX1. Recent work from Yang, Lindahl and Barnes has provided insight into the cellular consequence of TREX1-deficiency. They found that TREX1-deficiency resulted in the intracellular accumulation of single stranded DNA resulting in chronic activation of the DNA damage response network, even in cells from Trex1-mutated AGS patients. Here, I summarise their findings and discuss them in context with the other AGS causative genes which encode subunits of the RNase H2 complex. I describe mechanisms by which the inappropriate intracellular accumulation of nucleic acid species might deleteriously impact upon normal cell cycle progression. Finally, using the example of Systemic Lupus Erythematosus (SLE), I also summarise the evidence suggesting that the failure to process intermediates of nucleic acid metabolism can result in the activation of uncontrolled autoimmunity.
  • References (38)
    38 references, page 1 of 4

    [1] [2] [3] [4] J. Aicardi and F. Goutieres A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis., Ann Neurol 15 (1984) 49-54.

    Wassmer, B. Weschke, M.L. Whiteford, M.A.A. Willemsen, A. Zankl, S.M. Zuberi, S. Orcesi, E. Fazzi, P. Lebon and Y.J. Crow Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome, American journal of human genetics 81 (2007) 713-725.

    Till, J.L. Tolmie, P. Tomlin, T. Voit, B. Weschke, C.G. Woods, P. Lebon, D.T. Bonthron, C.P. Ponting and A.P. Jackson Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection, Nat Genet 38 (2006) 910-916.

    Cowan, S.G. Frints, J. Klepper, J.H. Livingston, S.A. Lynch, R.F. Massey, J.F. Meritet, J.L. Michaud, G. Ponsot, T. Voit, P. Lebon, D.T. Bonthron, A.P. Jackson, D.E. Barnes and T. Lindahl Mutations in the gene encoding the 3[prime]-5[prime] DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus, Nat Genet 38 (2006) 917-920.

    [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] Y.-G. Yang, T. Lindahl and D.E. Barnes Trex1 Exonuclease Degrades ssDNA to Prevent Chronic Checkpoint Activation and Autoimmune Disease, Cell 131 (2007) 873-886.

    D. Chowdhury, P.J. Beresford, P. Zhu, D. Zhang, J.-S. Sung, B. Demple, F.W. Perrino and J. Lieberman The Exonuclease TREX1 Is in the SET Complex and Acts in Concert with NM23-H1 to Degrade DNA during Granzyme A-Mediated Cell Death, Molecular Cell 23 (2006) 133-142.

    P.T. Tran, N. Erdeniz, L.S. Symington and R.M. Liskay EXO1-A multitasking eukaryotic nuclease, DNA Repair 3 (2004) 1549-1559.

    T. Lindahl, J.A. Gally and G.M. Edelman Deoxyribonuclease IV: A New Exonuclease from Mammalian Tissues, Proceedings of the National Academy of Sciences 62 (1969) 597-603.

    Y. Liu, H.-I. Kao and R.A. Bambara FLAP ENDONUCLEASE 1: A Central Component of DNA Metabolism, Annual Review of Biochemistry 73 (2004) 589-615.

    T. Lindahl, J.A. Gally and G.M. Edelman Properties of Deoxyribonuclease III from Mammalian Tissues, J. Biol. Chem. 244 (1969) 5014-5019.

  • Similar Research Results (1)
  • Metrics
    0
    views in OpenAIRE
    0
    views in local repository
    45
    downloads in local repository

    The information is available from the following content providers:

    From Number Of Views Number Of Downloads
    Sussex Research Online - IRUS-UK 0 45
Share - Bookmark