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The Innate Immune Response to DNA Damage Occurs in Live Intact Cells

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The Innate Immune Response to DNA Damage Occurs in Live Intact Cells THE CELL-INTRINSIC INNATE IMMUNE RESPONSE TO DNA DAMAGE IN HUMAN CELLS A thesis is submitted for the degree of Doctor of Philosophy Gillian Dunphy Department of Biomedical and Life Sciences Lancaster University 2017 I declare that this thesis is my own work and has not been submitted in part, or as a whole, for the award of a higher degree elsewhere. 1 Table of Contents List of Tables ........................................................................................................................5 List of Figures ......................................................................................................................6 Abstract ................................................................................................................................9 Acknowledgements............................................................................................................ 10 Abbreviations ..................................................................................................................... 11 Chapter 1: Introduction ...................................................................................................... 14 1.1 The DNA Damage Response ........................................................................................ 14 1.1.1 Introduction to DNA repair ....................................................................................... 14 1.1.2 DSBs and Topoisomerases ..................................................................................... 15 1.1.3 Double Strand Break Repair .................................................................................... 16 1.1.4 ATM and γH2AX ...................................................................................................... 18 1.1.5 P53 ......................................................................................................................... 20 1.1.6 PARP-1 ................................................................................................................... 21 1.1.7 DNA Damage and Cancer ....................................................................................... 22 1.2 The Innate Immune Response ..................................................................................... 24 1.2.1 The function of the innate immune system ............................................................... 24 1.2.2 TLRs ....................................................................................................................... 26 1.2.3 Inflammasomes ....................................................................................................... 28 1.2.4 RLRs ....................................................................................................................... 29 1.2.5 Intracellular dsDNA sensing ..................................................................................... 29 1.2.6 cGAS....................................................................................................................... 31 1.2.7 Other Intracellular DNA Sensors .............................................................................. 35 1.3 IFI16 .............................................................................................................................. 38 1.3.1 Structure.................................................................................................................. 38 1.3.2 IFI16 and the dsDNA response ................................................................................ 41 1.3.3 Senescence and Other Functions ............................................................................ 43 1.3.4 IFI16 in Disease....................................................................................................... 45 1.4 STING ............................................................................................................................ 47 1.4.1 STING Structure and Function ................................................................................. 47 1.4.2 Post-Translational Modifications of STING ............................................................... 50 1.4.3 Downstream Signalling of STING ............................................................................. 53 1.4.3 STING in Disease .................................................................................................... 54 1.5 Transcriptional responses to DNA sensing and DNA damage .................................. 56 1.5.1 NFκB ....................................................................................................................... 56 1.5.2 MAPKs .................................................................................................................... 60 2 1.5.3 IRFs ........................................................................................................................ 61 1.5.4 IFNs ........................................................................................................................ 62 1.5.5 Type-I IFN ............................................................................................................... 63 1.6 DNA Damage-Immune Overlap .................................................................................... 65 1.6.1 Evidence of an Immune Response to DNA Damage ................................................ 65 1.6.2 Interplay between DDR and Viruses ........................................................................ 66 1.6.3 The Immune Response and Cancer ......................................................................... 69 1.6.4 The DNA Damage Response in Autoimmunity ......................................................... 72 1.7 Project Aims ............................................................................................................... 73 Chapter 2 - Materials and Methods .................................................................................... 75 Chapter 3 – There is an innate immune response to DNA damage in human keratinocytes and fibroblasts ............................................................................................ 90 3.1 Etoposide-Induced DNA damage stimulates an innate immune response in human keratinocytes .................................................................................................................... 90 3.2 The innate immune response to DNA damage occurs in live intact cells ...................... 96 3.3 Etoposide-induced DNA damage stimulates an innate immune response in primary human keratinocytes ........................................................................................................ 99 3.4 Etoposide-induced DNA damage also stimulates an innate immune response in human fibroblasts and monocytes. ............................................................................................... 99 3.5 Various genotoxic agents induce an innate immune response in human keratinocytes ...................................................................................................................................... 101 3.6 Conclusions .............................................................................................................. 103 Chapter 4 – IFI16 is required for the innate immune response to DNA damage ........... 105 4.1 IFI16-deficient HaCaT cell characterisation ............................................................... 105 4.2 IFI16 is essential for the innate immune response to DNA damage in human keratinocytes .................................................................................................................. 108 4.3 IFI16 is essential for the innate immune response to other DNA damaging agents in human keratinocytes ...................................................................................................... 112 4.4 IFI16 is essential for the innate immune response to DNA damage in primary human keratinocytes. ................................................................................................................. 112 4.5 IFI16 is essential for the innate immune response to DNA damage in primary human fibroblasts....................................................................................................................... 115 4.6 Conclusions .............................................................................................................. 115 Chapter 5 – STING is required for the innate immune response to DNA damage ........ 116 5.1 Generating STING-deficient HaCaT cells and STING-deficient cell characterisation .. 116 5.2 STING is essential for the innate immune response to DNA damage ........................ 121 5.3 STING is essential for the innate immune response to DNA damage in primary keratinocytes .................................................................................................................. 124 5.4 STING is essential for the innate immune response to DNA damage in primary human fibroblasts ...................................................................................................................... 124 5.5 Conclusions .............................................................................................................. 124 Chapter 6 – cGAS is not required for the innate immune response to DNA damage ... 127 3 6.1 Generation of cGAS-deficient HaCaT cells ............................................................... 128 6.2 cGAS deficient cell response ...................................................................................
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