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<model id="M4790" metaid="fa912804-c86e-4b2d-9274-3c7482991267" name="Fanconi anemia and checkpoint recovery">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">The FA/BRCA pathway repairs DNA interstrand crosslinks. Mutations in this pathway cause Fanconi anemia (FA), a chromosome instability syndrome with bone marrow failure and cancer predisposition. Upon DNA damage, normal and FA cells inhibit the cell cycle progression, until the G2/M checkpoint is turned off by the checkpoint recovery, which becomes activated when the DNA damage has been repaired. Interestingly, highly damaged FA cells seem to override the G2/M checkpoint. In this study we explored with a Boolean network model and key experiments whether checkpoint recovery activation occurs in FA cells with extensive unrepaired DNA damage. Computational simulations suggested that in FA mutants checkpoint recovery activity inhibits the checkpoint components despite unrepaired DNA damage, a behavior that we did not observed in wild-type simulations. This result implies that FA cells would eventually reenter the cell cycle after a DNA damage induced G2/M checkpoint arrest, but before the damage has been fixed. We observed that FA-A cells activate the G2/M checkpoint and arrest in G2 phase, but eventually reach mitosis and divide with unrepaired DNA damage, thus resolving the initial checkpoint arrest. Based on our model result we look for ectopic activity of checkpoint recovery components. We found that checkpoint recovery components, such as PLK1, are expressed to a similar extent as normal undamaged cells do, even though FA-A cells harbor highly damaged DNA. Our results show that FA cells, despite extensive DNA damage, do not loss the capacity to express the transcriptional and protein components of checkpoint recovery that might eventually allow their division with unrepaired DNA damage. This might allow cell survival but increases the genomic instability inherent to FA individuals and promotes cancer.</body>
</notes>
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<vCard:Family>Crowther</vCard:Family>
<vCard:Given>Audrey</vCard:Given>
</vCard:N>
<vCard:EMAIL>audrey.crowther@huskers.unl.edu</vCard:EMAIL>
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<vCard:Orgname>University of Nebraska-Lincoln</vCard:Orgname>
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<dcterms:W3CDTF>2016-08-28T19:07:05Z</dcterms:W3CDTF>
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<dcterms:W3CDTF>2017-02-10T13:29:15Z</dcterms:W3CDTF>
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<rdf:li rdf:resource="urn:miriam:pubmed:26385365"/>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Ataxia Telangiectasia Mutated</p><p>UniProt ID: Q13315</p><p>Gene Name: ATM</p><p>Gene ID: 472</p></body>
</notes>
<annotation>
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<dcterms:W3CDTF>2016-12-07T12:24:10Z</dcterms:W3CDTF>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Checkpoint Recovery Process</p></body>
</notes>
<annotation>
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<rdf:Description rdf:about="#_31601cac-9e60-4595-ae09-ee1ecc128b65">
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<dcterms:W3CDTF>2016-11-09T09:54:23Z</dcterms:W3CDTF>
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<qual:qualitativeSpecies metaid="fdd649e3-2450-4841-a4f7-f10a7f369270" qual:compartment="cytosol" qual:constant="false" qual:id="S_3" qual:initialLevel="0" qual:maxLevel="1" qual:name="p53">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Cellular tumor antigen p53</p><p>Gene Name: TP53</p><p>UniProt ID: P04637</p><p>NCBI Gene ID: 7157</p></body>
</notes>
<annotation>
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<dcterms:W3CDTF>2016-12-19T10:17:29Z</dcterms:W3CDTF>
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<rdf:li rdf:resource="urn:miriam:pubmed:10766245"/>
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<qual:qualitativeSpecies metaid="_13c04961-fc7f-485d-b1ac-baae9e4a387f" qual:compartment="cytosol" qual:constant="false" qual:id="S_4" qual:initialLevel="0" qual:maxLevel="1" qual:name="ATR">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Gene Name: ATR</p><p>Ataxia Telangiectasia and Rad3-Related checkpoint protein</p><p>UniProt ID: Q13535</p><p>Gene ID: 545</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
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<dcterms:W3CDTF>2016-08-28T22:44:31Z</dcterms:W3CDTF>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Homologous Recombination repair</p><p>This node represents the alternative Homologous Recombination Repair Pathway</p></body>
</notes>
<annotation>
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<dcterms:W3CDTF>2017-02-10T13:17:43Z</dcterms:W3CDTF>
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<qual:qualitativeSpecies metaid="_46e5bd29-5a23-423e-b29e-afe8c813682d" qual:compartment="cytosol" qual:constant="false" qual:id="S_6" qual:initialLevel="0" qual:maxLevel="1" qual:name="FAcore">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FA core complex</p></body>
</notes>
<annotation>
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<rdf:Description rdf:about="#_46e5bd29-5a23-423e-b29e-afe8c813682d">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2016-12-07T12:24:10Z</dcterms:W3CDTF>
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</annotation>
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<qual:qualitativeSpecies metaid="_501ae15c-8eeb-432a-a609-2be22cf77e3a" qual:compartment="cytosol" qual:constant="false" qual:id="S_7" qual:initialLevel="0" qual:maxLevel="1" qual:name="FAHRR">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>This node represents the proteins that act in the Homologous Recombination Repair pathway, including FANCD1N, RAD51, HRR, ssDNARPA, FANCJMLH1, MRN, and BRCA1.</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_501ae15c-8eeb-432a-a609-2be22cf77e3a">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2016-12-19T09:02:15Z</dcterms:W3CDTF>
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<qual:qualitativeSpecies metaid="_08c790e0-2355-4892-b8e8-2693202e2edd" qual:compartment="cytosol" qual:constant="false" qual:id="S_8" qual:initialLevel="0" qual:maxLevel="1" qual:name="ADD">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>DNA adducts</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_08c790e0-2355-4892-b8e8-2693202e2edd">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2016-08-28T22:54:12Z</dcterms:W3CDTF>
</dcterms:modified>
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</rdf:RDF>
</annotation>
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<qual:qualitativeSpecies metaid="_0ce8301b-6e2d-4f53-89c5-2d602119c7b3" qual:compartment="cytosol" qual:constant="false" qual:id="S_9" qual:initialLevel="0" qual:maxLevel="1" qual:name="DSB	">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Double-strand break</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_0ce8301b-6e2d-4f53-89c5-2d602119c7b3">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-10T13:17:43Z</dcterms:W3CDTF>
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</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="_3489a96c-0268-42ec-b004-5d4f761cd1fb" qual:compartment="cytosol" qual:constant="false" qual:id="S_10" qual:initialLevel="0" qual:maxLevel="1" qual:name="TLS">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Proliferation cell nuclear antigen (PCNA), translesion synthesis (TLS)</p><p>Abbreviated from PCNATLS to TLS</p><p>UniProt AccessionID: P12004</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_3489a96c-0268-42ec-b004-5d4f761cd1fb">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-10T13:17:43Z</dcterms:W3CDTF>
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</annotation>
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<qual:qualitativeSpecies metaid="_745b3646-51dc-4c6f-a6a4-fbfe029b364b" qual:compartment="cytosol" qual:constant="false" qual:id="S_11" qual:initialLevel="0" qual:maxLevel="1" qual:name="NUC1">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Nuclease mediated ICL incision</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_745b3646-51dc-4c6f-a6a4-fbfe029b364b">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2016-12-19T10:17:29Z</dcterms:W3CDTF>
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</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="b67b8349-70f2-4b0a-b5a3-37d426ba3b51" qual:compartment="cytosol" qual:constant="false" qual:id="S_12" qual:initialLevel="0" qual:maxLevel="1" qual:name="ICL">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Interstrand cross links</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#b67b8349-70f2-4b0a-b5a3-37d426ba3b51">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-10T13:02:30Z</dcterms:W3CDTF>
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</annotation>
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<qual:qualitativeSpecies metaid="c3e9aa1e-c201-418f-809a-59bf4c4d0def" qual:compartment="cytosol" qual:constant="false" qual:id="S_13" qual:initialLevel="0" qual:maxLevel="1" qual:name="NUC2">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Nuclease mediated ICL incision</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#c3e9aa1e-c201-418f-809a-59bf4c4d0def">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-10T13:17:43Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="_0de4dbb7-c714-4239-91d1-4eb557ccbc05" qual:compartment="cytosol" qual:constant="false" qual:id="S_14" qual:initialLevel="0" qual:maxLevel="1" qual:name="FANCD2I">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Fanconi anemia group I protein/ Fanconi anemia group D2 protein</p><p>Gene Name: FANCI/FANCD2</p><p>UniProt ID: Q9NVI1/Q9BXW9</p><p>Gene ID: 55215/2175</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_0de4dbb7-c714-4239-91d1-4eb557ccbc05">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2016-12-19T09:02:15Z</dcterms:W3CDTF>
</dcterms:modified>
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</rdf:RDF>
</annotation>
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<qual:qualitativeSpecies metaid="_8ae54ef7-572c-42b9-b8c8-7302d06c5cbd" qual:compartment="cytosol" qual:constant="false" qual:id="S_15" qual:initialLevel="0" qual:maxLevel="1" qual:name="NHEJ">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>DNA End Joining Repair protein</p><p>For more info: http://www.ncbi.nlm.nih.gov/mesh/?term=nhej</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_8ae54ef7-572c-42b9-b8c8-7302d06c5cbd">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-10T13:02:30Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
</qual:listOfQualitativeSpecies>
<qual:listOfTransitions xmlns:qual="http://www.sbml.org/sbml/level3/version1/qual/version1">
<qual:transition qual:id="tr_S_1">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATR activates ATM.</p><p>DSB activates ATM.</p><p>CHKREC inhibits ATM.</p><p>FAcore inhibits ATM.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_1_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CHKREC activation leads to ATM dephosphorylation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_1_in_S_4" qual:qualitativeSpecies="S_4" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATR phosphorylates ATM.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_1_in_S_9" qual:qualitativeSpecies="S_9" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATM recognizes the nucleosome disruption caused by DSBs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_1_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The FA pathway is activated after ATM inhibition by KU-55933.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_1" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_4 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_2">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TLS, NHEJ, HRR2, or FAHRR activate sCHKREC.</p><p>CHKREC inactivates itself.</p><p>DSB inhbits CHKREC.</p><p>ADD inhibits CHKREC.</p><p>ICL inhibits CHKREC.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_2_in_S_5" qual:qualitativeSpecies="S_5" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The HRR pathway repairs DNA damage, which activates CHKREC.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_2_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The NHEJ pathway repairs DNA damage, which activates CHKREC.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_2_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CHKREC inactivates itself (Inferred interaction).</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_2_in_S_9" qual:qualitativeSpecies="S_9" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The absence of DSB allows for CHKREC activation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_2_in_S_7" qual:qualitativeSpecies="S_7" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The HRR pathway repairs DNA damage, which activates CHKREC.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_2_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The absence of ICL activates CHKREC (Inferred interaction).</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_2_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TLS allows for DNA replication to continue past the point of damage, which activates CHKREC.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_2_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The absence of ADD activates CHKREC (Inferred interaction).</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_2" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_7 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_7 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_3">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NHEJ, ATM, or ATR activates p53.</p><p>CHKREC inhibits p53.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_3_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CHKREC leads to the dephosphorylation of p53.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_3_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NHEJ positively regulates p53 through phosphorylation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_3_in_S_1" qual:qualitativeSpecies="S_1" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATM positively regulates p53 through phosphorylation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_3_in_S_4" qual:qualitativeSpecies="S_4" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATR positively regulates p53 through phosphorylation.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_3" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_4 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_4">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CHKREC inhibits ATR.</p><p>ATM activates ATR.</p><p>ICL activates ATR.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_4_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CHKREC inactivates ATR (Inferred interaction).</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_4_in_S_1" qual:qualitativeSpecies="S_1" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATM indirectly activates ATR.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_4_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Detection of ICL leads to ATR recuirment to the site of damage via ATRIP.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_4" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_5">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NHEJ in conjunction with ICL, DSB, and NUC2 activates HRR2.</p><p>FAHRR inhibits HRR2.</p><p>NHEJ inhibits HRR2.</p><p>TLS in conjunction with DSB and NUC2 activates HRR2.</p><p>CHKREC inhibits HRR2.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_5_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CHKREC indirectly inhibits HRR2.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="dual" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NHEJ is a pathway used to repair double-stranded breaks. The activation of NHEJ eliminates the need for the HRR2 pathway.</p><p>NHEJ can create DSB, activating HRR2.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NUC2 generates DSBs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_9" qual:qualitativeSpecies="S_9" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Detection of DSB activates HRR2.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_7" qual:qualitativeSpecies="S_7" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The alternative HRR pathway does not occur if FAHRR is functioning.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Detection of ICL activates HRR2</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TLS indirectly activates HRR2.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_5" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_7 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_7 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_6">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ICL in conjunction with ATM or ATR activates FAcore.</p><p>CHKREC negatively regulates FAcore.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_6_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>In mitosis, the FAcore is hyperphosphorylated, which induces its release from FANCM.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_1" qual:qualitativeSpecies="S_1" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATM recruits proteins involved in the FAcore complex.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_4" qual:qualitativeSpecies="S_4" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATR recruits proteins involved in the FAcore complex.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Detection of ICL leads to recruitment of the FAcore.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_6" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<or/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_4 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_7">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FANCD2I in conjunction with DSB activates FAHRR.</p><p>NHEJ in conjunction with CHKREC inhibits FAHRR.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_7_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NHEJ indirectly inhibits FAHRR.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_7_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CHKREC indirectly inhibits FAHRR.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_7_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Detection of DSB leads to monoubiquitination of FANCD2I, which causes its localized into chromatin-associated foci containing DNA replication and repair factors.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_7_in_S_9" qual:qualitativeSpecies="S_9" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Detection of DSB leads to monoubiquitination of FANCD2I, which causes its localized into chromatin-associated foci containing DNA replication and repair factors.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_7" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<not/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_8">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NUC1 and NUC2 activate ADD.</p><p>TLS inhibits ADD.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_8_in_S_11" qual:qualitativeSpecies="S_11" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NUC1 and NUC2 cleave DNA, creating ADDs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_8_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NUC1 and NUC2 cleave DNA, creating ADDs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_8_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TLS aids in repairing ADDs.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_8" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_11 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_11 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_9">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NUC2 activates DSB.</p><p>HRR2 inhibits DSB.</p><p>NHEJ inhibits DSB.</p><p>FAHRR inhibits DSB.</p><p>NUC1 activates DSB.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_9_in_S_5" qual:qualitativeSpecies="S_5" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>HRR2 repairs DSBs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_9_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NHEJ repairs DSBs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_9_in_S_11" qual:qualitativeSpecies="S_11" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NUC1 cleaves DNA, creating DSBs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_9_in_S_7" qual:qualitativeSpecies="S_7" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FAHRR repairs DSBs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_9_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NUC2 cleaves DNA, creating DSBs.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_9" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_7 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_11 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_7 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_10">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ADD activates TLS.</p><p>CHKREC inhibits TLS.</p><p>FAcore in conjunction with ADD activates TLS.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_10_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>In the absence of damage, PCNA is SUMOylated to inhibit TLS.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_10_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Detection of ADD causes the activation of TLS.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_10_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The FAcore channels DNA lesions into damage bypass pathways.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_10" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_11">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FANCD21 in conjunction with ICL activates NUC1.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_11_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FANCD21 recruits NUC1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_11_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FANCD21 in conjunction with ICL activates NUC1 through unhooking.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_11" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_12">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ICL activates itself.</p><p>DSB inhibits ICL.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_12_in_S_9" qual:qualitativeSpecies="S_9" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>DSB phophorylates ICL, which inhibits ICL.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_12_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ICL positively regulates itself (Inferred interaction).</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_12" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_13">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NUC1 in conjunction with p53 and ICL activates NUC2.</p><p>ICL in conjunction with ATM or ATR activates NUC2.</p><p>FAcore and FANCD21 activates NUC2.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_13_in_S_3" qual:qualitativeSpecies="S_3" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 is predicted to promote nuclease activity.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FANCD21 negatively regulates NUC2 through unhooking.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_11" qual:qualitativeSpecies="S_11" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Nuclease activity has a role in unhooking ICL lesions.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_1" qual:qualitativeSpecies="S_1" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATM phosphorylates downstream proteins to activate nuclease mediated ICL incision.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_4" qual:qualitativeSpecies="S_4" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATR phosphorylates downstream proteins to activate nuclease mediated ICL incision.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Nuclease activity has a role in unhooking ICL lesions.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FAcore indirectly negatively regulates NUC2.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_13" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_11 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_3 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<or/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_4 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_14">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FAcore in conjunction with ATM or ATR, or DSB with ATR or ATM activate FANCD21.</p><p>CHKREC inhibits FANCD21.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_14_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Upon repair of DNA damage, FANCD2 and FANCI dissociate.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_14_in_S_1" qual:qualitativeSpecies="S_1" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATM positively regulates FANCD2I through phosphorylation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_14_in_S_4" qual:qualitativeSpecies="S_4" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ATR positively regulates FANCD2I through phosphorylation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_14_in_S_9" qual:qualitativeSpecies="S_9" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The presence of DSB promotes FANCD2l to load onto chromatin.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_14_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FAcore ubiquitinates FANCD2I.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_14" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_4 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<or/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_4 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_15">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>DSB in conjuction with NUC2 activates NHEJ.</p><p>CHKREC, HRR2, or FAHRR inhibit NHEJ.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_15_in_S_5" qual:qualitativeSpecies="S_5" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>When HRR2 is active, NHEJ is not (two different repair mechanisms).</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_15_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CHKREC inhibits NHEJ through monoubiquiylation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_15_in_S_7" qual:qualitativeSpecies="S_7" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>FAHRR inhibits NHEJ through an interaction with Ku proteins.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_15_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NUC2 produces a substrate for NHEJ.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_15_in_S_9" qual:qualitativeSpecies="S_9" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Cleavage of DNA by NUC2 as a result of DSB activates NHEJ.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_15" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_9 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_7 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
</qual:listOfTransitions>
<listOfCompartments>
<compartment constant="true" id="cytosol" name="cytosol"/>
</listOfCompartments>
</model>
</sbml>