Cytosolic DNA and RNA can lead to innate immune sensing via three paths. DNA is sensed by cGAS, which activates STING. RNA is sensed by MDA5 and RIG-I, which activates MAVS. An activation of STING or MAVS lead to phosphorylation of IFR3, which triggers innate immune responses. This pathway was inspired by Chapter 14 of the 5th edition of the book of Blau (in press). The presence of ribonucleotides in genomic DNA enhances photodimerization of adjacent pyrimidines, which are repaired by nucleotide excision repair a42 cGAS which signals via STING (encoded by TMEM173) Catalytic subunit Cytosolic deoxyribonuclease anchored in the outer nuclear membrane. A lack of TREX1 causes DNA accumulation, both within the nucleus and the cytosol. Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing cb7 a96 DNA sensor mitochondrial antiviral signaling (MAVS) Single-stranded complementary DNA synthesized from an RNA template by the action of RNA-dependent DNA polymerase. Cytosolic RNA sensor Activating mutations in RIG-I and MDA5 increase receptor affinity resulting in constitutive type I IFN signaling. cytosolic RNA sensor Activating mutations in RIG-I and MDA5 increase receptor affinity resulting in constitutive type I IFN signaling. single-stranded DNA single-stranded DNA Noncatalytic subunit Noncatalytic subunit single-stranded DNA single-stranded DNA SAMHD1 has also ribonuclease activity, suggesting that a loss of SAMHD1 may lead to RNA accumulation. interferon-responsive genes Ribonucleotide RNase T2 degrades ribosomal RNA in lysosomes. A lack of RNase T2 causes RNA accumulation which may activate RNA sensors. Upon binding to dsRNA, OAS1 synthesizes 2′–5′-linked oligoadenylates using ATP as substrate, which in turn activate RNase L. Activation of RNase L leads to RNA degradation The heterotrimeric RNase H2 maintains genome integrity by removing ribonucleotides misincorporated during DNA replication The presence of ribonucleotides in genomic DNA enhances photodimerization of adjacent pyrimidines Within the cytosol, ssDNA metabolites with stem loops or dsDNA are sensed by the DNA sensor cGAS Binds ssDNA and degrades ssDNA derived from DNA repair "A photon causes two consecutive bases (Thymine or Cytosine) on one strand to bind together, destroying the normal base-pairing double-strand structure in that area." Source: [https://en.wikipedia.org/wiki/Pyrimidine_dimer] Transcription SAMHD1 degrades deoxynucleoside triphosphates (dNTP) induce type I IFN production activates expression of the IFNB gene and numerous interferon-responsive genes (ISG). Phosphorylation of the transcription factor interferon regulatory factor 3 (IRF3) ADAR modifies dsRNA through deamination of adenosine to inosine short RNA fragments that act as ligand for RIG-I Both RNA sensors, MDA5 and RIG-I signal via mitochondrial antiviral signaling (MAVS) to activate type I IFN Reverse transcribed Binds ssDNA and degrades cDNA from reverse transcription of endogenous retroelements Within the cytosol, ssDNA metabolites with stem loops or dsDNA are sensed by the DNA sensor cGAS Upon binding to dsRNA, OAS1 synthesizes 2′–5′-linked oligoadenylates using ATP as substrate, which in turn activate RNase L Activation of RNase L leads to formation of short RNA fragments that act as ligand for RIG-I Both RNA sensors, MDA5 and RIG-I signal via mitochondrial antiviral signaling (MAVS) to activate type I IFN "A lysosome is a membrane-bound cell organelle that contains digestive enzymes. Lysosomes are involved with various cell processes. They break down excess or worn-out cell parts." SOURCE: [https://www.genome.gov/genetics-glossary/Lysosome] 12618436 PubMed Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. J Biol Chem 2003 Cho DS Yang W Lee JT Shiekhattar R Murray JM Nishikura K 12368238 PubMed Mammalian retroelements. Genome Res 2002 Deininger PL Batzer MA signaling pathway in the innate immune response PW:0000819 Pathway Ontology altered DNA repair pathway PW:0000292 Pathway Ontology 7565688 PubMed 7565688 PubMed Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol Cell Biol 1995 Patterson JB Samuel CE