@prefix dcterms: .
@prefix ke-wp: .
@prefix mapping: .
@prefix xsd: .
mapping:0f78f083-ad48-4d0c-87d2-8d5b7c390286 a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-22T14:21:06.032583"^^xsd:dateTime ;
dcterms:identifier "0f78f083-ad48-4d0c-87d2-8d5b7c390286" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "high" ;
ke-wp:keyEventId "KE 1097" ;
ke-wp:keyEventName "Occurrence, renal proximal tubular necrosis" ;
ke-wp:pathwayDescription "Necrosis has traditionally been considered as a passive, unregulated cell death. However, accumulating evidence suggests that necrosis, like apoptosis, can be executed by genetically controlled and highly regulated cellular process that is morphologically characterized by a loss of cell membrane integrity, intracellular organelles and/or the entire cell swelling (oncosis) (Rello S et al. 2005; Galluzzi L et al. 2007; Berghe TV et al. 2014; Ros U et al. 2020). The morphological hallmarks of the nectotic death have been associated with different forms of programmed cell death including (but not limited to) parthanatos, necroptosis, glutamate-induced oxytosis, ferroptosis, inflammasome-mediated necrosis etc. Each of them can be triggered under certain pathophysiological conditions. For example UV, ROS or alkylating agents may induce poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation (parthanatos), while tumor necrosis factor (TNF) or toll like receptor ligands (LPS and dsRNA) can trigger necrosome-mediated necroptosis. The initiation events, e.g., PARP1 hyperactivation, necrosome formation, activation of NADPH oxidases, in turn trigger one or several common intracellular signals such as NAD+ and ATP-depletion, enhanced Ca2+ influx, dysregulation of the redox status, increased production of reactive oxygen species (ROS) and the activity of phospholipases. These signals affect cellular organelles and membranes leading to osmotic swelling, massive energy depletion, lipid peroxidation and the loss of lysosomal membrane integrity. Different mechanisms of permeabilization have emerged depending on the cell death form. Pore formation by gasdermins (GSDMs) is a hallmark of pyroptosis, while mixed lineage kinase domain-like (MLKL) protein facilitates membrane permeabilization in necroptosis, and phospholipid peroxidation leads to membrane damage in ferroptosis. This diverse repertoire of mechanisms leading to membrane permeabilization contributes to define the specific inflammatory and immunological outcome of each type of regulated necrosis. Regulated or programmed necrosis eventually leads to cell lysis and release of cytoplasmic content into the extracellular region that is often associated with a tissue damage resulting in an intense inflammatory response. The Reactome module describes necroptosis and pyroptosis." ;
ke-wp:pathwayName "Regulated Necrosis" ;
ke-wp:reactomeId "R-HSA-5218859" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" .
mapping:31ef20c0-9dd7-4a6c-96e2-fe226c52f871 a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-05-08T20:22:43.423053"^^xsd:dateTime ;
dcterms:identifier "31ef20c0-9dd7-4a6c-96e2-fe226c52f871" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "high" ;
ke-wp:keyEventId "KE 55" ;
ke-wp:keyEventName "Increase, Cell injury/death" ;
ke-wp:pathwayDescription "Activation of tumor necrosis factor receptor 1 (TNFR1) can trigger multiple signal transduction pathways to induce cell survival or cell death (Ward C et al. 1999; Micheau O and Tschopp J 2003; Widera D et al. 2006). While pro-survival signaling is initiated and regulated via the activated TNFR1 receptor complex at the cell membrane, cell death signals are induced upon the release of TRADD:TRAF2:RIP1 complex from the membrane to the cytosol where it forms death-inducing signaling complex (DISC) (Micheau O and Tschopp J 2003; Schneider-Brachert W et al. 2004). Upon apoptotic stimulation procaspase-8 or 10 is recruited into the DISC, and close proximity promotes the dimerization, autocatalytic processing, and activation of the initiator caspase-8 (and/or caspase-10) (Wang J et al. 2001; Boatright KM and Salvesen GS 2003). The initiator caspases then process and activate the downstream effector caspases such as caspase-3 in a proteolytic cascade (Stennicke HR et al. 1998). The effector caspases in turn cleave many diverse substrates, ultimately inducing cell death." ;
ke-wp:pathwayName "TNFR1-induced proapoptotic signaling" ;
ke-wp:reactomeId "R-HSA-5357786" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" ;
ke-wp:suggestionScore 0.5655 .
mapping:5230323d-1a23-4f54-ad71-032cf63b1622 a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-22T19:45:05.205831"^^xsd:dateTime ;
dcterms:identifier "5230323d-1a23-4f54-ad71-032cf63b1622" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "high" ;
ke-wp:keyEventId "KE 177" ;
ke-wp:keyEventName "Increase, Mitochondrial dysfunction" ;
ke-wp:pathwayDescription "Mitochondria are often described as the \"powerhouse\" of a cell as it is here that energy is largely released from the oxidation of food. Reducing equivalents generated from beta-oxidation of fatty acids and from the Krebs cycle enter the electron transport chain (also called the respiratory chain). During a series of redox reactions, electrons travel down the chain releasing their energy in controlled steps. These reactions drive the active transport of protons from the mitochondrial matrix , through the inner membrane to the intermembrane space. The respiratory chain consists of five main types of carrier; flavins, iron-sulfur centres, quinones, cytochromes (heme proteins) and copper. The two main reducing equivalents entering the respiratory chain are NADH and FADH2. NADH is linked through the NADH-specific dehydrogenase whereas FADH2 is reoxidised within succinate dehydrogenase and a ubiquinone reductase of the fatty acid oxidation pathway. Oxygen is the final acceptor of electrons and with protons, is converted to form water, the end product of aerobic cellular respiration. A proton electrochemical gradient (often called protonmotive force) is established across the inner membrane, with positive charge in the intermembrane space relative to the matrix. Protons driven by the proton-motive force, can enter ATP synthase thus returning to the mitochondrial matrix. ATP synthases use this exergonic flow to form ATP in the matrix, a process called chemiosmotic coupling. A by-product of this process is heat generation. An antiport, ATP-ADP translocase, preferentially exports ATP from the matrix thereby maintaining a high ADP:ATP ratio in the matrix. The tight coupling of electron flow to ATP synthesis means oxygen consumption is dependent on ADP availability (termed respiratory control). High ADP (low ATP) increases electron flow thereby increasing oxygen consumption and low ADP (high ATP) decreases electron flow and thereby decreases oxygen consumption. There are many inhibitors of mitochondrial ATP synthesis. Most act by either blocking the flow of electrons (eg cyanide, carbon monoxide, rotenone) or uncoupling electron flow from ATP synthesis (eg dinitrophenol). Thermogenin is a natural protein found in brown fat. Newborn babies have a large amount of brown fat and the heat generated by thermogenin is an alternative to ATP synthesis (and thus electron flow only produces heat) and allows the maintenance of body temperature in newborns. The electron transport chain is located in the inner mitochondrial membrane and comprises some 80 proteins organized in four enzymatic complexes (I-IV). Complex V generates ATP but has no electron transfer activity. In addition to these 5 complexes, there are also two electron shuttle molecules; Coenzyme Q (also known as ubiquinone, CoQ) and Cytochrome c (Cytc). These two molecules shuttle electrons between the large complexes in the chain. How many ATPs are generated by this process? Theoretically, for each glucose molecule, 32 ATPs can be produced. As electrons drop from NADH to oxygen in the chain, the number of protons pumped out and returning through ATP synthase can produce 2.5 ATPs per electron pair. For each pair donated by FADH2, only 1.5 ATPs can be formed. Twelve pairs of electrons are removed from each glucose molecule; 10 by NAD+ = 25 ATPs 2 by FADH2 = 3 ATPs. Making a total of 28 ATPs. However, 2 ATPs are formed during the Krebs' cycle and 2 ATPs formed during glycolysis for each glucose molecule therefore making a total ATP yield of 32 ATPs. In reality, the energy from the respiratory chain is used for other processes (such as active transport of important ions and molecules) so under conditions of normal respiration, the actual ATP yield probably does not reach 32 ATPs. The reducing equivalents that fuel the electron transport chain, namely NADH and FADH2, are produced by the Krebs cycle (TCA cycle) and the beta-oxidation of fatty acids. At three steps in the Krebs cycle (isocitrate conversion to oxoglutarate; oxoglutarate conversion to succinyl-CoA; Malate conversion to oxaloacetate), a pair of electrons (2e-) are removed and transferred to NAD+, forming NADH and H+. At a single step, a pair of electrons are removed from succinate, reducing FAD to FADH2. From the beta-oxidation of fatty acids, one step in the process forms NADH and H+ and another step forms FADH2. Cytoplasmic NADH, generated from glycolysis, has to be oxidized to reform NAD+, essential for glycolysis, otherwise glycolysis would cease to function. There is no carrier that transports NADH directly into the mitochondrial matrix and the inner mitochondrial membrane is impermeable to NADH so the cell uses two shuttle systems to move reducing equivalents into the mitochondrion and regenerate cytosolic NAD+. The first is the glycerol phosphate shuttle, which uses electrons from cytosolic NADH to produce FADH2 within the inner membrane. These electrons then flow to Coenzyme Q. Complex I is bypassed so only 1.5 ATPs can be formed per NADH via this route. The overall balanced equation, summing all the reactions in this system, is NADH (cytosol) + H+ (cytosol) + NAD+ (mito.) = NAD+ (cytosol) + NADH (mito.) + H+ (mito.) The malate-aspartate shuttle uses the oxidation of malate to generate NADH in the mitochondrial matrix. This NADH can then be fed directly to complex I and thus can form 3 ATPs via the respiratory chain. The overall balanced equation is NADH (cytosol) + H+ (cytosol) + FAD (inner memb.) = NAD+ (cytosol) + FADH2 (inner memb.) Both of these shuttle systems regenerate cytosolic NAD+. The entry point for NADH is complex I (NADH dehydrogenase) and the entry point for FADH2 is Coenzyme Q. The input of electrons from fatty acid oxidation via ubiquinone is complicated and not shown in the diagram." ;
ke-wp:pathwayName "Respiratory electron transport" ;
ke-wp:reactomeId "R-HSA-611105" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" .
mapping:68733506-b0fd-4b14-babf-8bf7ea07adb7 a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-22T14:21:10.075865"^^xsd:dateTime ;
dcterms:identifier "68733506-b0fd-4b14-babf-8bf7ea07adb7" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "medium" ;
ke-wp:keyEventId "KE 149" ;
ke-wp:keyEventName "Increase, Inflammation" ;
ke-wp:pathwayDescription "In contrast to NOD1/2 some NLRPs function as large macromolecular complexes called 'Inflammasomes'. These multiprotein platforms control activation of the cysteinyl aspartate protease caspase-1 and thereby the subsequent cleavage of pro-interleukin 1B (pro-IL1B) into the active proinflammatory cytokine IL1B. Activation of caspase-1 is essential for production of IL1B and IL18, which respectively bind and activate the IL1 receptor (IL1R) and IL18 receptor (IL18R) complexes. IL1R and IL18R activate NFkappaB and other signaling cascades. As the activation of inflammasomes leads to caspase-1 activation, inflammasomes can be considered an upstream step of the IL1R and IL18R signaling cascades, linking intracellular pathogen sensing to immune response pathways mediated by Toll-Like Receptors (TLRs). Monocytes and macrophages do not express pro-IL1B until stimulated, typically by TLRs (Franchi et al. 2009). The resulting pro-IL1B is not converted to IL1B unless a second stimulus activates an inflammasome. This requirement for two distinct stimuli allows tight regulation of IL1B/IL18 production, necessary because excessive IL-1B production is associated with numerous inflammatory diseases such as gout and rheumatoid arthritis (Masters et al. 2009). There are at least four subtypes of the inflammasome, characterized by the NLRP. In addition the protein AIM2 can form an inflammasome. All activate caspase-1. NLRP1 (NALP1), NLRP3 (Cryopyrin, NALP3), IPAF (CARD12, NLRC4) and AIM2 inflammasomes all have clear physiological roles in vivo. NLRP2, NLRP6, NLRP7, NLRP10 and NLRP12 have been demonstrated to modulate caspase-1 activity in vitro but the significance of this is unclear (Mariathasan and Monack, 2007). NLRP3 and AIM2 bind the protein 'apoptosis-associated speck-like protein containing a CARD' (ASC, also called PYCARD), via a PYD-PYD domain interaction. This in turn recruits procaspase-1 through a CARD-CARD interaction. NLRP1 and IPAF contain CARD domains and can bind procaspase-1 directly, though both are stimulated by ASC. Oligomerization of NLRPs is believed to bring procaspases into close proximity, leading to 'induced proximity' auto-activation (Boatright et al. 2003). This leads to formation of the active caspase tetramer. NLRPs are generally considered to be cytoplasmic proteins, but there is evidence for cytoplasmic-nuclear shuttling of the family member CIITA (LeibundGut-Landmann et al. 2004) and tissue/cell dependent NALP1 expression in the nucleus of neurons and lymphocytes (Kummer et al. 2007); the significance of this remains unclear." ;
ke-wp:pathwayName "Inflammasomes" ;
ke-wp:reactomeId "R-HSA-622312" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" .
mapping:71037286-2bae-4c9d-9b0d-cc536f2a5c0a a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-05-18T09:56:15.283980"^^xsd:dateTime ;
dcterms:identifier "71037286-2bae-4c9d-9b0d-cc536f2a5c0a" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "medium" ;
ke-wp:keyEventId "KE 177" ;
ke-wp:keyEventName "Increase, Mitochondrial dysfunction" ;
ke-wp:pathwayDescription "The mitochondrial pyruvate dehydrogenase (PDH) complex catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis. PDH inactivation is crucial for glucose conservation when glucose is scarce, while adequate PDH activity is required to allow both ATP and fatty acid production from glucose. The mechanisms that control human PDH activity include its phosphorylation (inactivation) by pyruvate dehydrogenase kinases (PDK 1-4) and its dephosphorylation (activation, reactivation) by pyruvate dehydrogenase phosphate phosphatases (PDP 1 and 2). Isoform-specific differences in kinetic parameters, regulation, and phosphorylation site specificity of the PDKs introduce variations in the regulation of PDC activity in differing endocrine and metabolic states (Sugden and Holness 2003). Further, PDH is inhibited by SIRT4 and the drug dichloroacetic acid (DCA)." ;
ke-wp:pathwayName "Regulation of pyruvate dehydrogenase (PDH) complex" ;
ke-wp:reactomeId "R-HSA-204174" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" ;
ke-wp:suggestionScore 0.7912 .
mapping:740dfd23-5797-4423-a8a4-4d5872814f70 a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-05-08T20:24:34.033794"^^xsd:dateTime ;
dcterms:identifier "740dfd23-5797-4423-a8a4-4d5872814f70" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "medium" ;
ke-wp:keyEventId "KE 55" ;
ke-wp:keyEventName "Increase, Cell injury/death" ;
ke-wp:pathwayDescription "Caspases, a family of cysteine proteases, execute apoptotic cell death. Caspases exist as inactive zymogens in cells and undergo a cascade of catalytic activation at the onset of apoptosis. Initiation of apoptosis occurs through either a cell-intrinsic or cell-extrinsic pathway. Extrinsic pathway cell death signals originate at the plasma membrane where: An extracellular ligand (e.g., FasL) binds to its cell surface transmembrane “death receptor” (e.g., Fas receptor), inducing oligomerization of the receptor (Trauth et al. 1989; Itoh and Nagata 1993; Danial and Korsmeyer 2004). The \"death receptors\" are specialized cell-surface receptors including Fas/CD95, tumor necrosis factor-alpha (TNF-alpha) receptor 1, and two receptors, DR4 and DR5, that bind to the TNF-alpha related apoptosis-inducing ligand (TRAIL). Ligand binding promotes clustering of proteins that bind to the intracellular domain of the receptor (e.g., FADD, or Fas-associated death domain-containing protein), which then binds to the prodomain of initiator caspases (e.g.caspase-8 or -10) to promote their dimerization and activation. Active caspase-8/-10 can then directly cleave and activate effector caspases, such as caspase-3 or it can cleave Bid, which facilitates mitochondrial cytochrome c release. Unique group of proteins termed dependence receptors (DpRs) transduce positive (often prosurvival or progrowth) signals when engaged by ligand, but emit proapoptotic signals in the absence of ligand (Goldschneider and Mehlen 2010). DpR family includes p75 neurotrophin receptor (p75NTR), deleted in colon cancer (DCC), and UNC5 homologs, among others. cell-surface membrane receptors." ;
ke-wp:pathwayName "Caspase activation via extrinsic apoptotic signalling pathway" ;
ke-wp:reactomeId "R-HSA-5357769" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" ;
ke-wp:suggestionScore 0.5641 .
mapping:a6bce6c0-8575-434c-8560-6bec2eb78ca8 a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-18T12:18:27.549953"^^xsd:dateTime ;
dcterms:identifier "a6bce6c0-8575-434c-8560-6bec2eb78ca8" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "medium" ;
ke-wp:keyEventId "KE 1194" ;
ke-wp:keyEventName "Increase, DNA damage" ;
ke-wp:pathwayDescription "Activated ATM phosphorylates a number of proteins involved in the DNA damage checkpoint and DNA repair (Thompson and Schild 2002, Ciccia and Elledge 2010), thereby triggering and coordinating accumulation of DNA DSB repair proteins in nuclear foci known as ionizing radiation-induced foci (IRIF). While IRIFs include chromatin regions kilobases away from the actual DSB site, this Reactome pathway represents simplified foci and events that happen proximal to the DNA DSB ends. In general, proteins localizing to the nuclear foci in response to ATM signaling are cooperatively retained at the DNA DSB site, forming a positive feedback loop and amplifying DNA damage response (Soutoglou and Misteli 2008). Activated ATM phosphorylates the NBN (NBS1) subunit of the MRN complex (MRE11A:RAD50:NBN) (Gatei et al. 2000), as well as the nucleosome histone H2AFX (H2AX) on serine residue S139, producing gamma-H2AFX (gamma-H2AX) containing nucleosomes (Rogakou et al. 1998, Burma et al. 2001). H2AFX is phosphorylated on tyrosine 142 (Y142) under basal conditions (Xiao et al. 2009). After ATM-mediated phosphorylation of H2AFX on S139, tyrosine Y142 has to be dephosphorylated by EYA family phosphatases in order for the DNA repair to proceed and to avoid apoptosis induced by DNA DSBs (Cook et al. 2009). Gamma-H2AFX recruits MDC1 to DNA DSBs (Stucki et al. 2005). After ATM phosphorylates MDC1 (Liu et al. 2012), the MRN complex, gamma-H2AFX nucleosomes, and MDC1 serve as a core of the nuclear focus and a platform for the recruitment of other proteins involved in DNA damage signaling and repair (Lukas et al. 2004, Soutoglou and Misteli 2008). RNF8 ubiquitin ligase binds phosphorylated MDC1 (Kolas et al. 2007) and, in cooperation with HERC2 and RNF168 (Bekker-Jensen et al. 2010, Campbell et al. 2012), ubiquitinates H2AFX (Mailand et al. 2007, Huen et al. 2007, Stewart et al. 2009, Doil et al. 2009) and histone demethylases KDM4A and KDM4B (Mallette et al. 2012). Ubiquitinated gamma-H2AFX recruits UIMC1 (RAP80), promoting the assembly of the BRCA1-A complex at DNA DSBs. The BRCA1-A complex consists of RAP80, FAM175A (Abraxas), BRCA1:BARD1 heterodimer, BRCC3 (BRCC36), BRE (BRCC45) and BABAM1 (MERIT40, NBA1) (Wang et al. 2007, Wang and Elledge 2007) Ubiquitin mediated degradation of KDM4A and KDM4B allows TP53BP1 (53BP1) to associate with histone H4 dimethylated on lysine K21 (H4K20Me2 mark) by WHSC1 at DNA DSB sites (Pei et al. 2011). Once recruited to DNA DSBs, both BRCA1:BARD1 heterodimers and TP53BP1 are phosphorylated by ATM (Cortez et al. 1999, Gatei et al. 2000, Kim et al. 2006, Jowsey et al. 2007), which triggers recruitment and activation of CHEK2 (Chk2, Cds1) (Wang et al. 2002, Wilson and Stern 2008, Melchionna et al. 2000). Depending on the cell cycle stage, BRCA1 and TP53BP1 competitively promote either homology directed repair (HDR) or nonhomologous end joining (NHEJ) of DNA DSBs. HDR through homologous recombination repair (HRR) or single strand annealing (SSA) is promoted by BRCA1 in association with RBBP8 (CtIP), while NHEJ is promoted by TP53BP1 in association with RIF1 (Escribano-Diaz et al. 2013)." ;
ke-wp:pathwayName "Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks" ;
ke-wp:reactomeId "R-HSA-5693565" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" ;
ke-wp:suggestionScore 0.7887 .
mapping:bbd1ec22-dc2a-4065-8cd8-3378ea7b0527 a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-22T19:45:03.493700"^^xsd:dateTime ;
dcterms:identifier "bbd1ec22-dc2a-4065-8cd8-3378ea7b0527" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "high" ;
ke-wp:keyEventId "KE 1194" ;
ke-wp:keyEventName "Increase, DNA damage" ;
ke-wp:pathwayDescription "DNA repair is a phenomenal multi-enzyme, multi-pathway system required to ensure the integrity of the cellular genome. Living organisms are constantly exposed to harmful metabolic by-products, environmental chemicals and radiation that damage their DNA, thus corrupting genetic information. In addition, normal cellular pH and temperature create conditions that are hostile to the integrity of DNA and its nucleotide components. DNA damage can also arise as a consequence of spontaneous errors during DNA replication. The DNA repair machinery continuously scans the genome and maintains genome integrity by removing or mending any detected damage. Depending on the type of DNA damage and the cell cycle status, the DNA repair machinery utilizes several different pathways to restore the genome to its original state. When the damage and circumstances are such that the DNA cannot be repaired with absolute fidelity, the DNA repair machinery attempts to minimize the harm and patch the insulted genome well enough to ensure cell viability. Accumulation of DNA alterations that are the result of cumulative DNA damage and utilization of \"last resort\" low fidelity DNA repair mechanisms is associated with cellular senescence, aging, and cancer. In addition, germline mutations in DNA repair genes are the underlying cause of many familial cancer syndromes, such as Fanconi anemia, xeroderma pigmentosum, Nijmegen breakage syndrome and Lynch syndrome, to name a few. When the level of DNA damage exceeds the capacity of the DNA repair machinery, apoptotic cell death ensues. Actively dividing cells have a very limited time available for DNA repair and are therefore particularly sensitive to DNA damaging agents. This is the main rationale for using DNA damaging chemotherapeutic drugs to kill rapidly replicating cancer cells. There are seven main pathways employed in human DNA repair: DNA damage bypass, DNA damage reversal, base excision repair, nucleotide excision repair, mismatch repair, repair of double strand breaks and repair of interstrand crosslinks (Fanconi anemia pathway). DNA repair pathways are intimately associated with other cellular processes such as DNA replication, DNA recombination, cell cycle checkpoint arrest and apoptosis. The DNA damage bypass pathway does not remove the damage, but instead allows translesion DNA synthesis (TLS) using a damaged template strand. Translesion synthesis allows cells to complete DNA replication, postponing the repair until cell division is finished. DNA polymerases that participate in translesion synthesis are error-prone, frequently introducing base substitutions and/or small insertions and deletions. The DNA damage reversal pathway acts on a very narrow spectrum of damaging base modifications to remove modifying groups and restore DNA bases to their original state. The base excision repair (BER) pathway involves a number of DNA glycosylases that cleave a vast array of damaged bases from the DNA sugar-phosphate backbone. DNA glycosylases produce a DNA strand with an abasic site. The abasic site is processed by DNA endonucleases, DNA polymerases and DNA ligases, the choice of which depends on the cell cycle stage, the identity of the participating DNA glycosylase and the presence of any additional damage. Base excision repair yields error-free DNA molecules. Mismatch repair (MMR) proteins recognize mismatched base pairs or small insertion or deletion loops during DNA replication and correct erroneous base pairing by excising mismatched nucleotides exclusively from the nascent DNA strand, leaving the template strand intact. Nucleotide excision repair pathway is involved in removal of bulky lesions that cause distortion of the DNA double helix. NER proteins excise the oligonucleotide that contains the lesion from the affected DNA strand, which is followed by gap-filling DNA synthesis and ligation of the repaired DNA molecule. Double strand breaks (DSBs) in the DNA can be repaired via a highly accurate homologous recombination repair (HRR) pathway, or through error-prone nonhomologous end joining (NHEJ), single strand annealing (SSA) and microhomology-mediated end joining (MMEJ) pathways. DSBs can be directly generated by some DNA damaging agents, such as X-rays and reactive oxygen species (ROS). DSBs can also be intermediates of the Fanconi anemia pathway. Interstrand crosslinking (ICL) agents damage the DNA by introducing covalent bonds between two DNA strands, which disables progression of the replication fork. The Fanconi anemia proteins repair the ICLs by unhooking them from one DNA strand. TLS enables the replication fork to bypass the unhooked ICL, resulting in two replicated DNA molecules, one of which contains a DSB and triggers double strand break repair, while the sister DNA molecule contains a bulky unhooked ICL, which is removed through NER. Single strand breaks (SSBs) in the DNA, generated either by DNA damaging agents or as intermediates of DNA repair pathways such as BER, are converted into DSBs if the repair is not complete prior to DNA replication. Simultaneous inhibition of DSB repair and BER through cancer mutations and anti-cancer drugs, respectively, is synthetic lethal in at least some cancer settings, and is a promising new therapeutic strategy. For reviews of DNA repair pathways, please refer to Lindahl and Wood 1999 and Curtin 2012." ;
ke-wp:pathwayName "DNA Repair" ;
ke-wp:reactomeId "R-HSA-73894" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" .
mapping:d0feeb32-b5f9-4ee6-9664-0d21a7baaafa a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-22T14:21:08.132454"^^xsd:dateTime ;
dcterms:identifier "d0feeb32-b5f9-4ee6-9664-0d21a7baaafa" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "high" ;
ke-wp:keyEventId "KE 1115" ;
ke-wp:keyEventName "Increase, Reactive oxygen species" ;
ke-wp:pathwayDescription "Reactive oxygen species such as superoxide (O2.-), peroxides (ROOR), singlet oxygen, peroxynitrite (ONOO-), and hydroxyl radical (OH.) are generated by cellular processes such as respiration (reviewed in Murphy 2009, Brand 2010) and redox enzymes and are required for signaling yet they are damaging due to their high reactivity (reviewed in Imlay 2008, Buettner 2011, Kavdia 2011, Birben et al. 2012, Ray et al. 2012). Aerobic cells have defenses that detoxify reactive oxygen species by converting them to less reactive products. Superoxide dismutases convert superoxide to hydrogen peroxide and oxygen (reviewed in Fukai and Ushio-Fukai 2011). Catalase and peroxidases then convert hydrogen peroxide to water. Humans contain 3 superoxide dismutases: SOD1 is located in the cytosol and mitochondrial intermembrane space, SOD2 is located in the mitochondrial matrix, and SOD3 is located in the extracellular region. Superoxide, a negative ion, is unable to easily cross membranes and tends to remain in the compartment where it was produced. Hydrogen peroxide, one of the products of superoxide dismutase, is able to diffuse across membranes and pass through aquaporin channels. In most cells the primary source of hydrogen peroxide is mitochondria and, once in the cytosol, hydrogen peroxide serves as a signaling molecule to regulate redox-sensitive proteins such as transcription factors, kinases, phosphatases, ion channels, and others (reviewed in Veal and Day 2011, Ray et al. 2012). Hydrogen peroxide is decomposed to water by catalase, decomposed to water plus oxidized thioredoxin by peroxiredoxins, and decomposed to water plus oxidized glutathione by glutathione peroxidases (Presnell et al. 2013)." ;
ke-wp:pathwayName "Detoxification of Reactive Oxygen Species" ;
ke-wp:reactomeId "R-HSA-3299685" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" .
mapping:d9d8ef95-e843-497d-a73a-ef7246e646bb a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-18T12:18:34.411354"^^xsd:dateTime ;
dcterms:identifier "d9d8ef95-e843-497d-a73a-ef7246e646bb" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "high" ;
ke-wp:keyEventId "KE 1392" ;
ke-wp:keyEventName "Oxidative Stress" ;
ke-wp:pathwayDescription "Subpathway representing cytoprotective genes regulated by NFE2L2 (NRF2). NFE2L2 is well-studied for its role in oxidative stress where it gets activated by ROS and then induces a plethora of gene expression regulation the oxidative damage. It induces genes/enzymes that regulate the phase 2 detoxification system (eg. GSTs and Glutathione system), ROS scavenging (SODs,PRDX1 ) and cytoprotection (HO1) by regulating inflammation and tissue damage (Tonelli et al, 2018; Shaw et al, 2020)" ;
ke-wp:pathwayName "NFE2L2 regulating anti-oxidant/detoxification enzymes" ;
ke-wp:reactomeId "R-HSA-9818027" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" ;
ke-wp:suggestionScore 0.85 .
mapping:db31062b-bf62-445e-b619-12df6956eded a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-22T14:21:12.108027"^^xsd:dateTime ;
dcterms:identifier "db31062b-bf62-445e-b619-12df6956eded" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "medium" ;
ke-wp:keyEventId "KE 149" ;
ke-wp:keyEventName "Increase, Inflammation" ;
ke-wp:pathwayDescription "Interleukins are low molecular weight proteins that bind to cell surface receptors and act in an autocrine and/or paracrine fashion. They were first identified as factors produced by leukocytes but are now known to be produced by many other cells throughout the body. They have pleiotropic effects on cells which bind them, impacting processes such as tissue growth and repair, hematopoietic homeostasis, and multiple levels of the host defense against pathogens where they are an essential part of the immune system." ;
ke-wp:pathwayName "Signaling by Interleukins" ;
ke-wp:reactomeId "R-HSA-449147" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" .
mapping:e0450bd4-3f1c-426f-b0d4-350290dfba86 a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-24T14:27:15.754434"^^xsd:dateTime ;
dcterms:identifier "e0450bd4-3f1c-426f-b0d4-350290dfba86" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "high" ;
ke-wp:keyEventId "KE 1287" ;
ke-wp:keyEventName "Glutathione synthesis" ;
ke-wp:pathwayDescription "The combination of glutamate, cysteine and ATP is required to form glutathione. The steps involved in the synthesis and recycling of glutathione are outlined (Meister, 1988)." ;
ke-wp:pathwayName "Glutathione synthesis and recycling" ;
ke-wp:reactomeId "R-HSA-174403" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" ;
ke-wp:suggestionScore 0.8366 .
mapping:fc84d976-c9bd-499e-9d9e-75a027446cb9 a ke-wp:KeyEventReactomeMapping ;
dcterms:creator "github:marvinm2" ;
dcterms:date "2026-07-18T12:18:31.084633"^^xsd:dateTime ;
dcterms:identifier "fc84d976-c9bd-499e-9d9e-75a027446cb9" ;
ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
ke-wp:confidenceLevel "medium" ;
ke-wp:keyEventId "KE 1825" ;
ke-wp:keyEventName "Increase, Cell death" ;
ke-wp:pathwayDescription "The tumor suppressor TP53 (p53) exerts its tumor suppressive role in part by regulating transcription of a number of genes involved in cell death, mainly apoptotic cell death. The majority of apoptotic genes that are transcriptional targets of TP53 promote apoptosis, but there are also several TP53 target genes that inhibit apoptosis, providing cells with an opportunity to attempt to repair the damage and/or recover from stress. Pro-apoptotic transcriptional targets of TP53 involve TRAIL death receptors TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2), as well as the FASL/CD95L death receptor FAS (CD95). TRAIL receptors and FAS induce pro-apoptotic signaling in response to external stimuli via extrinsic apoptosis pathway (Wu et al. 1997, Takimoto et al. 2000, Guan et al. 2001, Liu et al. 2004, Ruiz de Almodovar et al. 2004, Liu et al. 2005, Schilling et al. 2009, Wilson et al. 2013). IGFBP3 is a transcriptional target of TP53 that may serve as a ligand for a novel death receptor TMEM219 (Buckbinder et al. 1995, Ingermann et al. 2010). TP53 regulates expression of a number of genes involved in the intrinsic apoptosis pathway, triggered by the cellular stress. Some of TP53 targets, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1, regulate the permeability of the mitochondrial membrane and/or cytochrome C release (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013). Other pro-apoptotic genes, either involved in the intrinsic apoptosis pathway, extrinsic apoptosis pathway or pyroptosis (inflammation-related cell death), which are transcriptionally regulated by TP53 are cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10 (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007). It is uncertain how exactly some of the pro-apoptotic TP53 targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP contribute to apoptosis (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012). TP53 is stabilized in response to cellular stress by phosphorylation on at least serine residues S15 and S20. Since TP53 stabilization precedes the activation of cell death genes, the TP53 tetramer phosphorylated at S15 and S20 is shown as a regulator of pro-apoptotic/pro-cell death genes. Some pro-apoptotic TP53 target genes, such as TP53AIP1, require additional phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003). Additional post-translational modifications of TP53 may be involved in transcriptional regulation of genes presented in this pathway and this information will be included as evidence becomes available. Activation of some pro-apoptotic TP53 targets, such as BAX, FAS, BBC3 (PUMA) and TP53I3 (PIG3) requires the presence of the complex of TP53 and an ASPP protein, either PPP1R13B (ASPP1) or TP53BP2 (ASPP2) (Samuels-Lev et al. 2001, Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013), indicating how the interaction with specific co-factors modulates the cellular response/outcome. TP53 family members TP63 and or TP73 can also activate some of the pro-apoptotic TP53 targets, such as FAS, BAX, BBC3 (PUMA), TP53I3 (PIG3), CASP1 and PERP (Bergamaschi et al. 2004, Jain et al. 2005, Ihrie et al. 2005, Patel et al. 2008, Schilling et al. 2009, Celardo et al. 2013). For a review of the role of TP53 in apoptosis and pro-apoptotic transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015." ;
ke-wp:pathwayName "TP53 Regulates Transcription of Cell Death Genes" ;
ke-wp:reactomeId "R-HSA-5633008" ;
ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
ke-wp:reactomeReleaseVersion "96" ;
ke-wp:species "Homo sapiens" ;
ke-wp:suggestionScore 0.7706 .