MOTIVATION: Fanconi anemia (FA) is a chromosomal instability syndrome originated by inherited mutations that impair the Fanconi Anemia/Breast Cancer (FA/BRCA) pathway, which is committed to the repair of DNA interstrand cross-links (ICLs). The disease displays increased spontaneous chromosomal aberrations and hypersensitivity to agents that create DNA interstrand cross-links. In spite of DNA damage, FA/BRCA-deficient cells are able to progress throughout the cell cycle, probably due to the activity of alternative DNA repair pathways, or due to defects in the checkpoints that monitor DNA integrity. RESULTS: We propose a Boolean network model of the FA/BRCA pathway, Checkpoint proteins and some alternative DNA repair pathways. To our knowledge, this is the largest network model incorporating a DNA repair pathway. Our model is able to simulate the ICL repair process mediated by the FA/BRCA pathway, the activation of Checkpoint proteins observed by recurrent DNA damage, as well as the repair of DNA double-strand breaks and DNA adducts. We generated a series of simulations for mutants, some of which have never been reported and thus constitute predictions about the function of the FA/BRCA pathway. Finally, our model suggests alternative DNA repair pathways that become active whenever the FA/BRCA pathway is defective. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2012-04-13T12:45:01Z 2016-01-22T07:08:46Z

* (MUS81/EME1) a heterodimer with 3' endonuclease activity

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*DNA adducts

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<font face="Arial, Verdana" size="2">DNA End Joining Repair protein</font><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">For more info:</div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/?term=nhej</font></div>

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Ataxia Telangiectasia Mutated<div>UniProt ID: <a href="http://www.uniprot.org/uniprot/Q13315" style="font-size: 10pt; text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; line-height: 20.081974029541px; background-color: rgb(222, 239, 245);">Q13315</a></div><div>Gene Name: ATM</div><div>Gene ID: 472</div>

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*FANCM/FAAp24 protein complex<div><br/></div>

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Fanconi Anemia core complex

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*RAD51 is a downstream FA/BRCA pathway mutant cell

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Interstrand cross links

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H2AX histone

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DNA-activated protein kinase

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<font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Tumor protein </span><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">p53</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">[</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P04637" style="text-decoration: none; background-color: rgb(255, 255, 255);">P04637</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/7157" ref="ordinalpos=2&ncbi_uid=7157&link_uid=7157" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">TP53</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">7157</span></font></div>

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Checkpoint Recovery Process

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Proliferation cell nuclear antigen (PCNA), translesion synthesis (TLS)<div>PCNA (human)</div><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P12004" style="font-size: 10pt; text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; line-height: 20.0819721221924px; background-color: rgb(222, 239, 245);">P12004</a></div><div><br/></div><div><br/></div>

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*Double-strand breaks

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Single strand DNA Replication Protein A

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*Homologous recombination repair

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*FANCD1N is a downstream FA/BRCA pathway mutant cell

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*Ataxia Telangiectasia and Rad3-Related checkpoint protein<div>*ATR phosphorylates multiple FA/BRCA and FA/BRCA-associated proteins</div>

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*MRN exonuclease<div>*MRN acts only in absence of FA/BRCA and NHEJ pathways</div>

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<font face="Arial, Verdana" size="2">Checkpoint Kinase 1- an effector kinase</font><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/O14757" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">O14757</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">for more info:</div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/67081350</font></div>

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* 5 ' endonuclease

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BRCA1 protein<div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/Q3B891" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">Q3B891</a></div>

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FANCJBRCA1 protein

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KU70 an NHEJ protein

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<font face="Arial, Verdana" size="2" style="font-size: 10pt;">Checkpoint 2 kinase (human)</font><div><font size="2">UniProt AccessionID: </font><a href="http://www.uniprot.org/uniprot/O96017" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">O96017</a><font size="2"><br/></font><div style="font-size: 10pt; font-family: Arial, Verdana; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">for more info:</div><div style="font-size: 10pt;"><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68064447</font></div></div>

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<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ICL positively regulates MUS81 [1, 2]</span>

S_9 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ADD positively regulates ADD [1, 2, 3, 4]. MUS81 in conjunction with either FAN1 or XPF positively regulates ADD {[1] [2] [3] [4]} PCNATLS inhibits ADD [1, 2, 3, 4]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*PCNATLS negatively regulates ADD {[1] [2] [3] [4]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3;">*MUS81 in conjunction with either FAN1 or XPF positively regulates ADD {[1] [2] [3] [4]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ADD positively regulates itself {[1] [2] [3] [4]}</span>

S_2 1 S_14 1 S_1 1 S_5 1 S_23 1 S_14 1

DSB, DNAPK, and KU in conjunction positively regulate NHEJ [1, 2]. DSB, DNAPK, and XPF in conjunction positively regulate NHEJ [1, 2]. ATM and ATR in conjunction negatively regulate NHEJ in the presence of DSB, DNAPK, AND KU [1]. FANCJBRCA1 and ssDNARPA in conjunction negatively regulate NHEJ in the presence of DSB, DNAPK, and XPF [1]. CHKREC negatively regulates NHEJ in the presence of DSB, DNAPK, and XPF [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*FANCJBRCA1 and ssDNARPA act together to deactivate NHEJ in the presence of DSB, DNAPK, and XPF {[1]}</span>

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*DSB, DNAPK, and KU work together to activate NHEJ {[1] [2]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">*DSB, DANPK, and (Inferred interaction) XPF work in conjunction to activate NHEJ {[1] [2]}</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*DSB, DNAPK, and KU work together to activate NHEJ {[1] [2]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATM and ATR together inactivate NHEJ in the presence of DSB, DNAPK and KU {[1]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*CHKREC inactivates NHEJ in the presence of DSB, DNAPK, and XPF {[1]}</span>

S_5 1 S_15 1 S_11 1 S_25 1 S_16 1 S_13 1 S_26 1 S_15 1 S_11 1 S_4 1 S_20 1

ATR positively regulates ATM [1, 2, 3]. DSB positively regulates ATM [1, 2, 3]. CHKREC negatively regulates ATM [1, 2, 3].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATR or DSB positively regulate ATM {[1] [2] [3]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATR or DSB positively regulate ATM {[1] [2] [3]}</span>

S_15 1 S_13 1 S_20 1 S_13 1

S_12 1 S_1 1 S_7 1 S_23 1 S_17 1 S_1 1 S_6 1

<font color="#4f4f4f" face="Arial, sans-serif"><span style="font-size: 12px; line-height: 14.40000057220459px;">ICL positively regulates FANCM [1, 2, 3]. CHKREC negatively regulates FANCM [1, 2, 3].</span></font>

S_9 1 S_13 1

FANCM in conjunction with either ATM or ATR [1, 3, 4, 5]. CHKREC negatively regulates FAcore [1, 2, 3, 4, 5].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*FANCM recruits the FA core {[1] [2] [3] [4] [5]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Either ATM or ATR act in conjunction with FANCM to recruit the FA core complex {[1] [3] [4] [5]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">CHKREC negatively regulates the FAcore {[1] [3] [4] [5]}</span>

S_6 1 S_20 1 S_4 1 S_13 1

FANCD1N in conjunction with ssDNARPA positively regulate RAD51 [1, 2, 3, 4]. CHKREC negatively regulates RAD51 [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*FANCD1N and ssDNARPA activate the RAD51 complex {[1] [2] [3] [[4]}</span>

S_16 1 S_19 1 S_13 1

ICL can activate itself, and DSB is a dominant negative regulator.<br>

DSB phophorylates ICL which inhibits ICL. [1] <br>

S_9 1 S_15 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">DSB and either ATM or ATR or DNAPK activates H2AX [1, 2, 3, 4]. CHKREC negatively regulates H2AX [1, 2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">*DSB and either ATM or ATR or DNAPK activates H2AX {[1] [2]}</span>

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*After the DSB has been generated, the H2AX histone becomes phosphorylated {[3] [4]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">*DSB and either ATM or ATR or DNAPK activates H2AX {[1] [2]}</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*DSB and either ATM or ATR or DNAPK activates H2AX {</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">[1] [2]</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*CHKREC negatively regulates H2AX {</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">[1] [2]</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">}</span>

S_15 1 S_11 1 S_20 1 S_4 1 S_13 1

DSB in conjunction with KU positively regulate DNAPK [1, 2, 3, 4]. CHKREC negatively regulates DNAPK [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">* If the DSB site is occupied by the KU proteins, the Artemis-DNAPKcs complex will be activated {[1] [2] [3] [4]}</span>

S_15 1 S_26 1 S_13 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATR and CHK1 act in conjunction to positively regulate p53 {[1] [2] [3] [4]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATM and CHK2 act in conjunction to positively regulate p53 {[1] [2] [3] [4]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATR and CHK1 act in conjunction to positively regulate p53 {[1] [2] [3] [4]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATM and CHK2 act in conjunction to positively regulate p53 {[1] [2] [3] [4]}</span>

S_20 1 S_22 1 S_13 1 S_4 1 S_27 1 S_13 1 S_11 1 S_13 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">PCNATLS or NHEJ or HRR in combination with the absence of DSB will activate CHKREC (Inferred interaction) [1]. CHKREC inactivates itself [1]. DSB negatively regulates CHKREC [1, 2, 3, 4]. ADD negatively regulates CHKREC [1]. ICL negatively regulates CHKREC [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*The absence of ICL will activate CHKREC (Inferred interaction) {[1]}</span>

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*The absence of DSB will activate CHKREC {[1] [2] [3] [4]} </p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">*PCNATLS or NHEJ or HRR in combination with the absence of DSB will activate CHKREC (Inferred interaction) {[1]}</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*The absence of ADD will activate CHKREC (Inferred interaction) {[1]}</span>

S_14 1 S_15 1 S_3 1 S_15 1 S_18 1 S_15 1 S_14 1 S_9 1 S_15 1 S_2 1 S_18 1 S_13 1 S_3 1

ADD positively regulates PCNATLS [1, 2, 3, 4]. ADD in conjunction with FAcore positively regulates PCNATLS [1, 2, 3, 4, 5]. FAN1 in conjunction with USP1 negatively regulates PCNATLS [1, 2, 3].

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*USP1 inactivates PCNA proteins by deubiquitination {[1] [2] [3]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">*FAN1 and USP1 act together to negatively regulate PCNATLS (Inferred Interaction) {[1]}</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ADD in combination with FAcore can activate PCNATLS {[1] [2] [3] [4] [5]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*FAN1 and USP1 act together to negatively regulate PCNATLS (Inferred Interaction) {[1]}</span>

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*The simulation of an ADD causes the activation of PCNATLS pathway {[1] [2] [3] [4]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">*ADD in combination with FAcore can activate PCNATLS {[1] [2] [3] [4] [5]}</div>

S_7 1 S_2 1 S_28 1 S_23 1 S_2 1 S_28 1 S_23 1

DSB positively regulates DSB [1, 2, 3, 4]. FAN1 positively regulates DSB [1, 2, 3, 4]. XPF positively regulates DSB [1, 2, 3, 4]. HRR negatively regulates DSB [1, 2, 3, 4]. NHEJ negatively regulates DSB [1, 2, 3, 4].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Either DSB, XPF, or FAN1 activates DSB {[1] [2] [3] [4]}</span>

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*XPF has a positive interaction over DSB (Inferred interaction) {[1]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">Either DSB, XPF, or FAN1 activates DSB {[1] [2] [3] [4]}</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Either HRR or NHEJ negatively regulate DSB {[1] [2] [3] [4]}</span>

S_15 1 S_18 1 S_3 1 S_5 1 S_18 1 S_3 1 S_23 1 S_18 1 S_3 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">DSB with the combination of FANCD2I and FANCJBRCA1 will activate ssDNARPA [1, 2]. DSB in conjunction with MRN will positively regulate ssDNARPA [1, 2]. KU in conjunction with RAD51 positively regulates ssDNARPA [1, 2].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*DSB in conjunction with MRN will activate ssDNARPA {[1] [2]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*The presence of RAD51 or KU (Inferred interaction) will inactivate ssDNARPA {[1] [2]}</span>

S_15 1 S_21 1 S_25 1 S_17 1 S_8 1 S_26 1

FAcore in conjunction with either ATM or ATR positively regulates FANCD2I [1, 2, 7, 8, 9]. DSB in conjunction with H2AX positively regulates FANCD2I [1, 7, 8 9]. USP1 negatively regulates FANCD2I [1, 3, 4, 5, 6, 7, 8, 9].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*H2AX and DSB work in conjunction to activate FANCD2I {[1] [7] [8] [9]}</span>

It is known that the USP1 deubiquitinating protein is able to inactivate the FANCD2I complex [1, 3, 4, 5, 6, 7, 8, 9]

The FAcore complex monoubiquitinates the FANCD2I complex [1, 2, 7, 8, 9]<div><span style="orphans: 3; widows: 3;">*Either ATR or ATM act in conjunction with the FAcore to positively regulate FANCD2I {[1] [7] [8] [9]}</span></div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Either ATR or ATM act in conjunction with the FAcore to positively regulate FANCD2I {[1] [7] [8] [9]}</span>

S_7 1 S_20 1 S_4 1 S_10 1 S_15 1 S_28 1

BRCA1 in conjunction with DSB and RAD51 and FANCD1N positively regulates HRR [1, 2, 3, 4, 5]. CHKREC negatively regulates HRR [1].

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*FANCD1 is implicated in HRR, facilitating an error-free repair process {[1] [3]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);"><span style="line-height: 24px; orphans: 3; widows: 3;">*DSB and RAD51 and FANCD1n and BRCA1 activate HRR {[1] [4] [5]}</span></div>

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*BRCA1 mediates the HRR pathway {[1] [2] [3]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);"><span style="line-height: 24px; orphans: 3; widows: 3;">*DSB and RAD51 and FANCD1n and BRCA1 activate HRR {[1] [4] [5]}</span></div>

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*RAD51 complex is implicated in HRR, facilitating an error-free repair process {[1] [3]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);"><span style="line-height: 24px; orphans: 3; widows: 3;">*DSB and RAD51 and FANCD1n and BRCA1 activate HRR {[1] [4] [5]}</span></div>

S_15 1 S_19 1 S_24 1 S_8 1 S_13 1

ssDNARPA and either BRCA1 or FANCD2I positively regulate FAND1N [1, 2, 3, 4]. CHKREC negatively regulates FANCD1N [1, 2, 3, 4].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ssDNARPA acts in conjuction with either BRCA1 or FANCD2I to activate the FANCD1N pathway {[1] [2] [3] [4]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ssDNARPA acts in conjuction with either BRCA1 or FANCD2I to activate the FANCD1N pathway {[1] [2] [3] [4]}</span>

S_16 1 S_24 1 S_17 1 S_16 1 S_13 1

ATM positively regulates ATR [1, 2, 3, 4]. FANCM positively regulates ATR [1, 2, 3, 4]. ssDNARPA positively regulates ATR [1, 2, 3, 4]. CHKREC negatively regulates ATR [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATM or FANCM or ssDNARPA positively regulates ATR {[1] [2] [3] [4]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATM or FANCM or ssDNARPA positively regulates ATR {[1] [2] [3] [4]}</span>

S_4 1 S_13 1 S_6 1 S_13 1 S_16 1 S_13 1

ATM in conjunction with DSB positively regulate MRN [1, 2, 3]. CHKRECand RAD51 independently negatively regulate MRN [1]. , FACND2I and KU in conjunction negatively regulate MRN [1].

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*KU <span style="line-height: 24px;">negatively regulates MRN (Inferred interaction) {[1]}</span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);"><span style="line-height: 24px; orphans: 3; widows: 3;">*KU70 works in conjunction with FANCD2I complex to inhibit MRN {[1]}</span></div>

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*FANCD2I <span style="line-height: 24px;">negatively regulates MRN (Inferred interaction) {[1]}</span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);"><span style="line-height: 24px; orphans: 3; widows: 3;">*KU70 works in conjunction with FANCD2I complex to inhibit MRN {[1]}</span></div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*RAD51 </span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; orphans: 3; widows: 3; line-height: 24px; background-color: rgb(255, 255, 255);">negatively regulates MRN (Inferred interaction) {[1]}</span>

S_15 1 S_4 1 S_13 1 S_26 1 S_17 1 S_8 1

ATM positively regulates CHK1 [1, 2, 3]. ATR positively regulates CHK1 [1, 2, 3]. DNAPK positively regulates CHK1 [1, 2, 3]. CHKREC negatively regulates CHK1 [1, 2, 3].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATM or ATR or DNAPK positively regulates CHK1 {[1] [2] [3]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATM or ATR or DNAPK positively regulates CHK1 {[1] [2] [3]}</span>

S_11 1 S_13 1 S_20 1 S_13 1 S_4 1 S_13 1

MUS81 and FANCD2I in conjunction positively regulate FAN1 [1, 2, 3].

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*The monoubiquitinated FANCD2I complex recruits FAN1 {[1] [2] [3]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);"><span style="line-height: 24px; orphans: 3; widows: 3;">*MUS81 and FANCD2I work in conjunction to positively regulate FAN1 {[1] [2] [3]}</span></div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*MUS81 and FANCD2I work in conjunction to positively regulate FAN1 {[1] [2] [3]}</span>

S_1 1 S_17 1

DSB in conjunction with either ATM or CHK2 or ATR positively regulates BRCA1 [1, 2, 3, 4, 5]. CHKREC negatively regulates BRCA1 [1].

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);">*ATR phosphorylates BRCA {[1] [2]}</p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">*DSB in conjunction with either ATM or CHK2 or ATR activates BRCA1 pathway {[1] [3] [4] [5]}</div>

S_15 1 S_27 1 S_20 1 S_4 1 S_13 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Either ATM or ATR act in conjunction with either ICL or ssDNARPA to activate FANCJBRCA1 [1, 2, 3].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Either ATM or ATR act in conjunction with either ICL or ssDNARPA to activate FANCJBRCA1 {[1] [2] [3]}</span>

S_16 1 S_20 1 S_4 1 S_9 1 S_20 1 S_4 1

DSB activates KU, whereas CHREC, FANCD2I, or MRN inhibit KU.

DSB is a positive regulator of KU [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*MRN or FANCD2I or CHKREC can inactivate KU {[[1] [2] [3] [4]}</span>

S_15 1 S_17 1 S_21 1 S_13 1

ATM positively regulates CHK2 [1, 2, 3, 4]. ATR positively regulates CHK2 [1, 2, 3, 4]. DNAPK positively regulates CHK2 [1, 2, 3, 4]. CHKREC negatively regulates CHK2 [1, 2, 3, 4].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ATM or ATR or DNAPK positively regulates CHK2 {[1] [2] [3] [4]}</span>

S_4 1 S_13 1 S_11 1 S_13 1 S_20 1 S_13 1

S_14 1 S_6 1 S_19 1 S_17 1 S_6 1