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

DNA Repair
Mark O'Driscoll

Abstract

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.

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Citations

Jan 9, 2009·British Medical Bulletin·S OrcesiE Fazzi
Mar 31, 2015·International Journal of Molecular Medicine·Weiguo SuiYong Dai
Jul 21, 2009·DNA Repair·Chuan-Jen WangYung-Chi Cheng
Sep 3, 2011·Immunological Reviews·Glen N Barber
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Apr 10, 2015·The Journal of Biological Chemistry·Fenghua YuanYanbin Zhang
Sep 6, 2020·Molecular Cancer·Yang WangXiawei Wei
Jul 1, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Laura E NogesPhilippa Marrack
Aug 14, 2018·Molecular Immunology·Alicia Martinez-LopezFelipe Diaz-Griffero
Jul 3, 2020·DNA Repair·Sean R SimpsonFred W Perrino
Jul 16, 2020·Immunity·Sarah M McWhirter, Caroline A Jefferies

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