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Machine Learning Discoveries of FANCD2-X Synergy in etc-1922159 Treated Colorectal Cancer Cells

Submitted:

09 January 2025

Posted:

13 January 2025

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Abstract
Fanconi anemia complementation group D2 (FANCD2) is one of the members of FA complementation group, that is activated in response to DNA damage and is involved in DNA repair and regulation of genomic stability. FANCD2 works with other members of FANC group along with other proteins/genes, to carry out its required functionality. Further, disruption of FA/BRCA pathway has been implicated in cancer progression. In colorectal cancer (CRC) cells treated with ETC-1922159, FANCD2 was found to be down regulated along with other genes. A recently developed search engine ranked combinations of FANCD2-X (X, a particular gene/protein) at 2nd order level after drug administration. Some of these combinations have been tested and established in wet lab, however many have been pointed out by the search engine that are yet to be explored/tested. These rankings reveal which FANCD2-X combinations might be working synergistically in CRC. In this research work, I cover combinations of FANCD2 with, REV3 like DNA directed polymerase zeta catalytic subunit (REV3L), Bloom syndrome RecQ like helicase (BLM), MRE11 homolog double strand break repair nuclease (MRE11A), Wnt family member 10B (WNT10B), ubiquitin like with PHD and ring finger domains 1 (UHRF1), hes family bHLH transcription factor 1 (HES1), BRCA DNA repair associated (BRCA), RAD51 recombinase (RAD51), ERCC excision repair endonuclease non-catalytic subunit (ERCC), KIAA, X-ray repair cross com- plementing (XRCC), structural maintenance of chromosomes (SMC), WD repeat do- main containing (WDR), ubiquitin conjugating enzyme E2 (UBE2), cell division cycle (CDC), importin (IPO), aldehyde dehydrogenase family member (ALDH), H2A variant histone (H2A), heat shock protein (HSP), cyclin dependent kinase (CDK), dynein axonemal heavy chain (DNAH), forkhead box (FOX), ring finger protein (RNF), E2F transcription factor (E2F) and small nucleolar RNA host gene (SNHG) family.
Keywords: 
FANCD2
;  
Porcupine inhibitor ETC-1922159
;  
Sensitivity analysis
;  
Colorectal cancer
Subject: 
Computer Science and Mathematics  -   Mathematical and Computational Biology

1. Introduction

1.1. Fanconi Anemia

Fanconi anemia (FA) is an autosomal recessive genetic disease that causes impaired response to DNA damage in the FA/BRCA pathway. FA was first described in 1927 by Guido Fanconi. D’Andrea [1] give a perspective on the role of FA complementation group proteins that are encoded by FANC genes. Briefly, D’Andrea [1] sumarizes the basic working background of the FA/BRCA pathway as follows - The FA proteins (A, C, E, F, G) are assembled in a nuclear protein complex along with BLM as a subunit. This complex is then required for the monoubiquitination of the downstream FANCD2. Next, monoubiquitinated FANCD2 assembles with the breast cancer susceptibility proteins, BRCA1 and BRCA2. The nuclear foci also contain the RAD51 and the MRE11/RAD50/NBS1 (M/R/N) complex. Disruption of genes in this pathway results in cellular hypersensitivity to DNA cross-linking agents, chromosome instability, and a propensity to cancer progression.

1.2. FANCD2

Houghtaling et al. [2] via FANCD2 knockout experiments in mice, showed that cellular sensitivity to DNA interstrand cross-links, perinatal lethality, germ cell loss, epithelial cancers and microphthalmia. Their work provides the first molecular link between the FA pathway and epithelial cancers. van Twest et al. [3] provide a detailed biochemical analysis and mechanistic basis of FANCI and FANCD2 monoubiquitination by the FA complex. They show that FANCB dimer coordinates the FANCD2 and FANCI monoubiquitination by two FANCL RING-ligases. FANCD2 was found to be down regulated in colorectal cancer cell lines after the treatment of ETC-1922159 drug, along with other genes, as observed in Madan et al. [4]. Many of the combinations of FANCD2 with other genes have been tested, established and reported in wet lab experiments, however there remain a range of combinations that are yet to be explored and tested. It would be nice to observe if there is any connection between the independently observed factors in the form of unknown biological hypotheses. To solve the issue, the next section discusses a solution to the problem.

1.3. Combinatorial search problem and a possible solution

In a recently published work Sinha [5], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Readers are requested to go through the adaptation of the above mentioned work for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC-1922159, Sinha [6]. The work uses SVM package by Joachims [7] in https://www.cs.cornell.edu/people/tj/svm_light/svm_rank.html. I use the adaptation to rank 2nd order gene combinations.

2. Results & Discussion

2.1. FANCD2 Related Synergies

2.1.1. FANCD2 - REV3L / BLM / MRE11A / WNT10B / UHRF1 / HES1

Bhat et al. [8] observe that experimental depletion of REV3 leads to increase in anaphase bridges, common fragile site (CFS) expression and chromosomal breaks/gaps. The genomic instability induced by REV3 depletion results in increased metaphase-specific FANCD2 foci formation and FANCD2 positive anaphase bridges, thus showing a connection between REV3 and FANCD2. Pichierri et al. [9] show that BLM and FANCD2 colocalise and co-immunoprecipitate in response to crosslinked DNA and stalled replication forks. Also, BLM and the FA core complex are both necessary for the assembly of the MRE11 complex. Further, the connection between MRE11 and FANCD2 is established as Roques et al. [10] show that inhibition of MRE11, NBS1 or RAD50 leads to a destabilization of FANCD2. Kaur et al. [11] found that FANCD2 was dependent on WNT/ β -catenin signaling in WNT-high cancers, and treatment with a PORCN inhibitor creates a BRCA-like state. FA pathway is critical for the response to toxic DNA interstrand crosslinks (ICLs). Liang et al. [12] showed that reduction of cellular levels of UHRF1 by RNAi attenuates the FA pathway and knockdown cells cause a reduction in FANCD2 foci formation. They observed that UHRF1 is required for the recruitment of FANCD2 to ICLs, which allows the DNA repair process to initiate. Finally, Tremblay et al. [13] show that HES1 is an interactor of FA core complex and is required for FANCD2 monoubiquitination. Taken together, all these experiments show a direct connection/synergy of the involved members with FANCD2. In colorectal cancer cells treated with ETC-1922159, these individual members (or their variants) and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of individial members and FANCD2, that were down regulated.
Table 1 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 2 generated from analysis of the ranks in Table 1. The Table 1 shows rankings of individual members w.r.t FANCD2. BLM - FANCD2 shows low ranking of 184 (laplace) and 305 (rbf). WNT10B - FANCD2 shows low ranking of 365 (laplace) and 307 (rbf). UHRF1 - FANCD2 shows low ranking of 1356 (laplace), 880 (linear) and 1268 (rbf). HES6 - FANCD2 shows low ranking of 1495 (laplace), 1182 (linear) and 1192 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, REV3L and MRE11A showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 1 graphically, with the following influences - • INDIVIDUAL family w.r.t FANCD2 with FANCD2 − > BLM, FANCD2 − > WNT10B, FANCD2 − > UHRF1, and FANCD2 − > HES6; .

2.1.2. FANCD2 - BRCA

DNA damage activates FA pathway, leading to monoubiquitination of FANCD2 protein and targeting nuclear foci containing BRCA1. Taniguchi et al. [14] show that this monoubiquitinated FANCD2 colocalizes with BRCA1 and RAD51 in S-phase–specific nuclear foci. Similar interaction was reported by Garcia-Higuera et al. [15]. Roy et al. [16] discuss that both BRCA1 and BRCA2 work in a common pathway, however they work at different stages in DNA damage response (DDR). BRCA1 functions in both checkpoint activation and DNA repair, while BRCA2 is a mediator of homologous recombination. In colorectal cancer cells treated with ETC-1922159, these BRCA family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of BRCA members and FANCD2, that were down regulated.
Table 3 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 4 generated from analysis of the ranks in Table 3. The Table 3 shows rankings of individual members w.r.t FANCD2. BRCA2 - FANCD2 shows low ranking of 354 (laplace) and 377 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, BRCA1 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 3 graphically, with the following influences - • BRCA family w.r.t FANCD2 with FANCD2 − > BRCA2.

2.1.3. FANCD2 - RAD51

Based on the previous section where it was cited that Taniguchi et al. [14] show that the monoubiquitinated FANCD2 colocalizes with BRCA1 and RAD51 in S-phase–specific nuclear foci, it can be assumed that there is a synergy between RAD51 and FANCD2. In colorectal cancer cells treated with ETC-1922159, these RAD51 family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of RAD51 members and FANCD2, that were down regulated.
Table 5 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 6 generated from analysis of the ranks in Table 5. The Table 5 shows rankings of individual members w.r.t FANCD2. RAD51 - FANCD2 shows low ranking of 885 (laplace) and 1383 (rbf). RAD51AP1 - FANCD2 shows low ranking of 644 (linear) and 1291 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, RAD51C showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 5 graphically, with the following influences - • RAD51 family w.r.t FANCD2 with FANCD2 − > RAD-51/51AP1.

2.1.4. FANCD2 - ERCC

ERCC1 is identified as a participant in nucleotide excision repair and has a possible relationship with FA pathway. McCabe et al. [17] show that the lack of FANCD2 focus formation is greater with depletion of ERCC1 than the lack of monoubiquitinated FANCD2 formation. This suggests a relation between ERCC1 and FANCD2 and in particular FA pathway. In colorectal cancer cells treated with ETC-1922159, these ERCC family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of ERCC members and FANCD2, that were down regulated.
Table 7 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 8 generated from analysis of the ranks in Table 7. The Table 7 shows rankings of individual members w.r.t FANCD2. ERCC8 - FANCD2 shows low ranking of 371 (laplace) and 997 (rbf). ERCC6L - FANCD2 shows low ranking of 1209 (laplace) and 520 (linear). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
One can also interpret the results of the Table 7 graphically, with the following influences - • ERCC family w.r.t FANCD2 with FANCD2 − > ERCC-8/6L.

2.1.5. FANCD2 - KIAA

Kikuno et al. [18] document a range of over 2000 novel human genes that are designated KIAA plus a four-digit number. MacKay et al. [19] describe a highly conserved protein, KIAA1018 that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2. In colorectal cancer cells treated with ETC-1922159, these KIAA family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of KIAA members and FANCD2, that were down regulated.
Table 9 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 10 generated from analysis of the ranks in Table 9. The Table 9 shows rankings of individual members w.r.t FANCD2. KIAA0586 - FANCD2 shows low ranking of 211 (laplace), 703 (linear) and 17 (rbf). KIAA1524 - FANCD2 shows low ranking of 225 (laplace) and 481 (rbf). KIAA1257 - FANCD2 shows low ranking of 749 (laplace), 1173 (linear) and 587 (rbf). KIAA0020 - FANCD2 shows low ranking of 979 (laplace) and 1332 (rbf). KIAA1324 - FANCD2 shows low ranking of 1466 (laplace), 413 (linear) and 1410 (rbf). KIAA1731 - FANCD2 shows low ranking of 1549 (laplace) and 1592 (linear). KIAA1586 - FANCD2 shows low ranking of 1233 (linear) and 277 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, KIAA0101, KIAA1143, KIAA1244 and KIAA1430 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 9 graphically, with the following influences - • KIAA family w.r.t FANCD2 with FANCD2 − > KIAA-0586 / 1524 / 1257 / 0020 / 1324 / 1731 / 1586.

2.1.6. FANCD2 - XRCC

XRCC2 is one of five somatic RAD51 paralogs and Andreassen and Hanenberg [20] state it appears to function downstream in the FA pathway, as it is not required for FANCD2 monoubiquitination. In colorectal cancer cells treated with ETC-1922159, these XRCC family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of XRCC members and FANCD2, that were down regulated.
Table 11 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 12 generated from analysis of the ranks in Table 11. The Table 11 shows rankings of individual members w.r.t FANCD2. XRCC6BP1 - FANCD2 shows low ranking of 1545 (linear) and 1200 (rbf). XRCC2 - FANCD2 shows low ranking of 111 (linear) and 1269 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, XRCC1 and XRCC6 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 11 graphically, with the following influences - • XRCC family w.r.t FANCD2 with FANCD2 − > XRCC-6BP1/2.

2.1.7. FANCD2 - SMC

Rossi et al. [21] show that SMC5 functions downstream of FANCD2 ubiquitylation with FANCC and SMC5/6 acts jointly with FANCD2 to mediate DNA repair and prevent genomic instability in human cells. Thus there is synergy between SMC and FANCD2. In colorectal cancer cells treated with ETC-1922159, these SMC family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of SMC members and FANCD2, that were down regulated.
Table 13 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 14 generated from analysis of the ranks in Table 13. The Table 13 shows rankings of individual members w.r.t FANCD2. SMC1A - FANCD2 shows low ranking of 1156 (laplace), 88 (linear) and 1502 (rbf). SMC4 - FANCD2 shows low ranking of 44 (laplace) and 83 (rbf). SMC2 - FANCD2 shows low ranking of 229 (laplace) and 236 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
One can also interpret the results of the Table 13 graphically, with the following influences - • SMC family w.r.t FANCD2 with FANCD2 − > SMC-1A/4/2.

2.1.8. FANCD2 - WDR

Gurtan et al. [22] show that point mutations in the WD40 repeats of FANCL disrupt FA core complex and FANCD2 mono-ubiquitination. Further, WD40 region of FANCL interacts with the FA complex and this correlates with the level of FANCD2 mono-ubiquitination. In colorectal cancer cells treated with ETC-1922159, these WDR family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of WDR members and FANCD2, that were down regulated.
Table 15 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 16 generated from analysis of the ranks in Table 15. The Table 15 shows rankings of individual members w.r.t FANCD2. WDR76 - FANCD2 shows low ranking of 34 (laplace) and 575 (rbf). WDR62 - FANCD2 shows low ranking of 162 (laplace) and 765 (rbf). WDR74 - FANCD2 shows low ranking of 344 (laplace), 501 (linear) and 615 (rbf). WDR12 - FANCD2 shows low ranking of 403 (laplace) and 870 (rbf). WDR77 - FANCD2 shows low ranking of 544 (laplace), 1480 (linear) and 402 (rbf). WDR75 - FANCD2 shows low ranking of 563 (laplace) and 805 (linear). WDR36 - FANCD2 shows low ranking of 623 (laplace) and 1159 (rbf). WDR43 - FANCD2 shows low ranking of 738 (laplace) and 1464 (rbf). WDR91 - FANCD2 shows low ranking of 1069 (laplace), 1180 (linear) and 976 (rbf). WDR35 - FANCD2 shows low ranking of 1162 (laplace), 1042 (linear) and 109 (rbf). WDR92 - FANCD2 shows low ranking of 1228 (laplace) and 427 (rbf). WDR18 - FANCD2 shows low ranking of 1234 (laplace) and 924 (linear). WDR3 - FANCD2 shows low ranking of 1562 (laplace) and 344 (linear). WDR89 - FANCD2 shows low ranking of 1297 (linear) and 749 (rbf). WDR90 - FANCD2 shows low ranking of 1462 (linear) and 785 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, WDR41, WDR70, WDR27, WDR5, WDR46, WDR61 and WDR53 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 15 graphically, with the following influences - • WDR family w.r.t FANCD2 with FANCD2 − > WDR-76 / 62 / 74 / 12 / 77 / 75 / 36 / 43 / 91 / 35 / 92 / 18 / 3 / 89 / 90.

2.1.9. FANCD2 - UBE2

Machida et al. [23] show that UBE2T is the ubiquitin-conjugating enzyme (E2) essential for FA pathway as it binds to FANCL , (the ubiquitin ligase subunit of the FA core complex) and is required for the monoubiquitination of FANCD2 in vivo. In colorectal cancer cells treated with ETC-1922159, these UBE2 family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of UBE2 members and FANCD2, that were down regulated.
Table 17 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 18 generated from analysis of the ranks in Table 17. The Table 17 shows rankings of individual members w.r.t FANCD2. UBE2G2 - FANCD2 shows low ranking of 137 (laplace), 1276 (linear) and 183 (rbf). UBE2S - FANCD2 shows low ranking of 506 (laplace), 1347 (linear) and 635 (rbf). UBE2T - FANCD2 shows low ranking of 689 (laplace) and 266 (linear). UBE2C - FANCD2 shows low ranking of 829 (laplace), 108 (linear) and 1505 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
One can also interpret the results of the Table 17 graphically, with the following influences - • UBE2 family w.r.t FANCD2 with FANCD2 − > UBE2-G2/S/T/C.

2.1.10. FANCD2 - CDC

Zhang et al. [24] show that CDC5L is required for the activation of downstream mediators of ATR checkpoint function such as FANCD2, CHK1 and RAD17. In colorectal cancer cells treated with ETC-1922159, these CDC family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of CDC members and FANCD2, that were down regulated.
Table 19 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 20 generated from analysis of the ranks in Table 19. The Table 19 shows rankings of individual members w.r.t FANCD2. CDCA2 - FANCD2 shows low ranking of 133 (laplace) and 329 (rbf). CDC25C - FANCD2 shows low ranking of 241 (laplace) and 76 (rbf). CDC6 - FANCD2 shows low ranking of 386 (laplace), 1327 (linear) and 14 (rbf). CDC25A - FANCD2 shows low ranking of 481 (laplace), 885 (linear) and 421 (rbf). CDCA7L - FANCD2 shows low ranking of 818 (laplace) and 1111 (rbf). CDCA8- FANCD2 shows low ranking of 909 (laplace), 1454 (linear) and 1220 (rbf). CDC7 - FANCD2 shows low ranking of 1269 (laplace), 695 (linear) and 1147 (rbf). CDCA7 - FANCD2 shows low ranking of 862 (linear) and 1373 (rbf). CDC20 - FANCD2 shows low ranking of 1088 (linear) and 1552 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, CDCA4, CDCA5, CDC45, CDC123, CDCA3 and CDC23 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 19 graphically, with the following influences - • CDC family w.r.t FANCD2 with FANCD2 − > CDC-A2 / 25C / 6 / 25A / A7L / A8 / 7 / A7.

2.1.11. FANCD2 - IPO

Wang et al. [25] demonstrate that C/EBP δ promotes monoubiquitination of FANCD2, by showing that the former interacts with FANCD2 and IPO4, thus mediating FANCD2–IPO4 association and augmenting nuclear import of FANCD2, which is a prerequisite for its monoubiquitination. In colorectal cancer cells treated with ETC-1922159, these IPO family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of IPO members and FANCD2, that were down regulated.
Table 21 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 22 generated from analysis of the ranks in Table 21. The Table 21 shows rankings of individual members w.r.t FANCD2. IPO11 - FANCD2 shows low ranking of 1040 (laplace) and 40 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, IPO5 and IPO9 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 21 graphically, with the following influences - • IPO family w.r.t FANCD2 with FANCD2 − > IPO-11.

2.1.12. FANCD2 - ALDH

Meng et al. [26] showed that ALDH1A1-knockdown resulted in decrease of KLF4 and p21 protein levels which caused S and G2 phase accumulation of cells. This increase in S and G2 cells shoed increased expression of FANCD2 and FANCJ. Thus, their results showed a correlation between ALDH1A1 and FANCD2. In colorectal cancer cells treated with ETC-1922159, these ALDH family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of ALDH members and FANCD2, that were down regulated.
Table 23 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 24 generated from analysis of the ranks in Table 23. The Table 23 shows rankings of individual members w.r.t FANCD2. ALDH3A1 - FANCD2 shows low ranking of 376 (laplace) and 543 (rbf). ALDH5A1 - FANCD2 shows low ranking of 419 (laplace), 1502 (linear) and 1249 (rbf). ALDH7A1 - FANCD2 shows low ranking of 581 (laplace), 1068 (linear) and 1352 (rbf). ALDH1B1 - FANCD2 shows low ranking of 262 (linear) and 1139 (rbf). ALDH9A1 - FANCD2 shows low ranking of 728 (linear) and 1157 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, ALDH3A2 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 23 graphically, with the following influences - • ALDH family w.r.t FANCD2 with FANCD2 − > ALDH-3A1/5A1/7A1/1B1/9A1.

2.1.13. FANCD2 - H2A

Bogliolo et al. [27] showed that phosphorylated H2AX was required for recruiting FANCD2 to chromatin at stalled replication forks. This binding of FANCD2 to phosphorylated H2AX is BRCA1-dependent. In colorectal cancer cells treated with ETC-1922159, these H2A family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of H2A members and FANCD2, that were down regulated.
Table 25 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 26 generated from analysis of the ranks in Table 25. The Table 25 shows rankings of individual members w.r.t FANCD2. H2AFX (or H2AX) - FANCD2 shows low ranking of 593 (laplace) and 324 (linear). H2AFV - FANCD2 shows low ranking of 791 (laplace), 1329 (linear). H2AFZ - FANCD2 shows low ranking of 1292 (laplace) and 634 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
One can also interpret the results of the Table 25 graphically, with the following influences - • H2A family w.r.t FANCD2 with FANCD2 − > H2A-FX/FV/FZ.

2.1.14. FANCD2 - HSP

Oda et al. [28] showed that HSP90 associated with FANCA, and disruption of this association by treatment with 17-AAG induces proteasomal degradation and cytoplasmic relocalization of FANCA, which lead to impaired activation of FANCD2. Thus there is an established connection between HSP90 and FANCD2. In colorectal cancer cells treated with ETC-1922159, these HSP family members and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of HSP members and FANCD2, that were down regulated.
Table 27 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 28 generated from analysis of the ranks in Table 27. The Table 27 shows rankings of individual members w.r.t FANCD2. HSPE1 - FANCD2 shows low ranking of 336 (laplace), 1246 (linear) and 745 (rbf). HSPD1 - FANCD2 shows low ranking of 385 (laplace), 388 (linear) and 617 (rbf). HSPB6 - FANCD2 shows low ranking of 1000 (laplace) and 520 (rbf). HSPA9 - FANCD2 shows low ranking of 370 (linear) and 1514 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, HSPA4L and HSP4A showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 27 graphically, with the following influences - • HSP family w.r.t FANCD2 with FANCD2 − > HSP-E1/D1/B6/A9.

2.1.15. FANCD2 - CDK

Blazek et al. [29] show that a variant of cyclin-CDK complex namely CYCK/CDK12 regulated expression of a small subset of human genes. Depletion of CYCK/CDK12 resulted in decreased expression of BRCA1, FANCD2, ATR and FANCI. Via this regulation, it is thought that the CYCK/CDK12 protects the cells from genomic instability. In colorectal cancer cells treated with ETC-1922159, these CDK family member and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of CDK members and FANCD2, that were down regulated.
Table 29 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 30 generated from analysis of the ranks in Table 29. The Table 29 shows rankings of individual members w.r.t FANCD2. CDK5RAP1 - FANCD2 shows low ranking of 1305 (laplace), 566 (linear) and 1196 (rbf). CDK5RAP2 - FANCD2 shows low ranking of 34 (linear) and 921 (rbf). CDK6 - FANCD2 shows low ranking of 337 (linear) and 1409 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, CDK4 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 29 graphically, with the following influences - • CDK family w.r.t FANCD2 with FANCD2 − > CDK-6/5RAP1/5RAP2.

2.1.16. FANCD2 - DNAH

Chang et al. [30] show involvement of DNAH2 in the regulation of ubiquitination and nuclear localization of FANCD2 upon the DNA damage. In colorectal cancer cells treated with ETC-1922159, these DNAH family member and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of DNAH members and FANCD2, that were down regulated.
Table 31 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 32 generated from analysis of the ranks in Table 31. The Table 31 shows rankings of individual members w.r.t FANCD2. DNAH11 - FANCD2 shows low ranking of 762 (laplace), 1463 (linear) and 567 (rbf). DNAH14 - FANCD2 shows low ranking of 1252 (laplace) and 229 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
One can also interpret the results of the Table 31 graphically, with the following influences - • DNAH family w.r.t FANCD2 with FANCD2 − > DNAH-11/14.

2.1.17. FANCD2 - FOX

Li et al. [31] report the functional interaction of FANCD2 and the forkhead transcription factor forkhead box (FOX) O3a i.e FOXO3A. FOXO3A formed a complex with FANCD2 foci in response to oxidative stress. In colorectal cancer cells treated with ETC-1922159, these FOX family member and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of FOX members and FANCD2, that were down regulated.
Table 33 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 34 generated from analysis of the ranks in Table 33. The Table 33 shows rankings of individual members w.r.t FANCD2. FOXJ1 - FANCD2 shows low ranking of 830 (laplace) and 972 (rbf). FOXD2-AS1 - FANCD2 shows low ranking of 1154 (laplace) and 611 (linear). FOXM1 - FANCD2 shows low ranking of 44 (linear) and 1142 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, FOXA2 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 33 graphically, with the following influences - • FOX family w.r.t FANCD2 with FANCD2 − > FOX-J1/D2-AS1/M1.

2.1.18. FANCD2 - RNF

Yan et al. [32] show that FAAP20 binds the ubiquitin product of RNF8-UBC13. RNF8-FAAP20 cascade is needed for efficient FANCD2 monoubiquitination. In colorectal cancer cells treated with ETC-1922159, these RNF family member and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of RNF members and FANCD2, that were down regulated.
Table 35 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 36 generated from analysis of the ranks in Table 35. The Table 35 shows rankings of individual members w.r.t FANCD2. RNF157-AS1 - FANCD2 shows low ranking of 399 (laplace) and 533 (linear). RNF166 - FANCD2 shows low ranking of 659 (laplace) and 526 (rbf). RNF20 - FANCD2 shows low ranking of 1227 (laplace), 247 (linear) and 1331 (rbf). RNF26 - FANCD2 shows low ranking of 1476 (laplace), 873 (linear) and 1540 (rbf). RNF144B - FANCD2 shows low ranking of 1504 (laplace) and 1095 (rbf). RNF157 - FANCD2 shows low ranking of 1553 (laplace), 417 (linear) and 449 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, RNF220 and RNF43 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 35 graphically, with the following influences - • RNF family w.r.t FANCD2 with FANCD2 − > RNF-157-AS1/166/20/26/144B/157.

2.1.19. FANCD2 - E2F

Mitxelena et al. [33] showed that E2F7 modulates the DNA repair program as knockdown experiment of E2F7 lead to a reduction in 53BP1 and FANCD2 foci. In colorectal cancer cells treated with ETC-1922159, these E2F family member and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of E2F members and FANCD2, that were down regulated.
Table 37 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 38 generated from analysis of the ranks in Table 37. The Table 37 shows rankings of individual members w.r.t FANCD2. E2F1 - FANCD2 shows low ranking of 200 (laplace) and 469 (rbf). E2F2 - FANCD2 shows low ranking of 472 (laplace) and 140 (rbf). E2F7 - FANCD2 shows low ranking of 482 (laplace) and 985 (rbf). E2F8 - FANCD2 shows low ranking of 192 (linear) and 582 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, E2F5 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 37 graphically, with the following influences - • E2F family w.r.t FANCD2 with FANCD2 − > E2F-1/2/7/8.

2.1.20. FANCD2 - SNHG

In hepatocellular carcinoma, [34] showed that SNHG1 upregulated the expression of FANCD2 and G6PD, thus inhibiting ferroptosis. In colorectal cancer cells treated with ETC-1922159, these SNHG family member and FANCD2, were found to be down regulated and recorded independently. I was able to rank 2nd order combinations of SNHG members and FANCD2, that were down regulated.
Table 39 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 40 generated from analysis of the ranks in Table 39. The Table 39 shows rankings of individual members w.r.t FANCD2. SNHG3 - FANCD2 shows low ranking of 339 (laplace) and 1259 (linear) SNHG6 - FANCD2 shows low ranking of 551 (laplace) and 74 (rbf). SNHG10 - FANCD2 shows low ranking of 866 (laplace) and 1442 (rbf). SNHG5 - FANCD2 shows low ranking of 1140 (laplace) and 674 (rbf). SNHG7 - FANCD2 shows low ranking of 1220 (laplace) and 694 (linear) SNHG17 - FANCD2 shows low ranking of 1524 (laplace), 454 (linear) and 1198 (rbf). SNHG15 - FANCD2 shows low ranking of 1464 (linear) and 322 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
Further, SNHG16, SNHG1, SNHG18 and SNHG8 showed high ranking with FANCD2, thus indicating that they might not be working synergistically with FANCD2, before the drug treatment.
One can also interpret the results of the Table 39 graphically, with the following influences - • SNHG family w.r.t FANCD2 with FANCD2 − > SNHG-3/6/10/5/7/17/15.

3. Conclusion

Presented here are a range of multiple synergistic FANCD2 2nd order combinations that were ranked via a machine learning based search engine. Via majority voting across the ranking methods, it was possible to find plausible unexplored synergistic combinations of FANCD2-X that might be prevalent in CRC cells after treatment with ETC-1922159 drug.

Author Contributions

Concept, design, in silico implementation - SS. Analysis and interpretation of results - SS. Manuscript writing - SS. Manuscript revision - SS. Approval of manuscript - SS.

Data Availability Statement

Data used in this research work was released in a publication in Madan et al. [4].

Acknowledgments

Special thanks to Mrs. Rita Sinha and Mr. Prabhat Sinha for supporting the author financially, without which this work could not have been made possible.

Conflicts of Interest

There are no conflicts to declare.

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Table 1. 2nd order interaction ranking between FANCD2 VS INDIVIDUAL family members.
Table 1. 2nd order interaction ranking between FANCD2 VS INDIVIDUAL family members.
Ranking INDIVIDUAL members VS FANCD2
Ranking of INDIVIDUAL members w.r.t FANCD2
laplace linear rbf
REV3L - FANCD2 1872 1049 2677
BLM - FANCD2 184 2738 305
MRE11A - FANCD2 2042 1744 1344
WNT10B - FANCD2 365 1891 307
UHRF1 - FANCD2 1356 880 1268
HES6 - FANCD2 1495 1182 1192
Table 2. 2nd order combinatorial hypotheses between FANCD2 and INDIVIDUAL family members.
Table 2. 2nd order combinatorial hypotheses between FANCD2 and INDIVIDUAL family members.
Unexplored combinatorial hypotheses
INDIVIDUAL members w.r.t FANCD2
BLM / WNT10B / UHRF1 / HES6 FANCD2
Table 3. 2nd order interaction ranking between FANCD2 VS BRCA family members.
Table 3. 2nd order interaction ranking between FANCD2 VS BRCA family members.
Ranking BRCA members VS FANCD2
Ranking of BRCA members w.r.t FANCD2
laplace linear rbf
BRCA2 - FANCD2 354 2668 377
BRCA1 - FANCD2 1772 244 2238
Table 4. 2nd order combinatorial hypotheses between FANCD2 and BRCA family members.
Table 4. 2nd order combinatorial hypotheses between FANCD2 and BRCA family members.
Unexplored combinatorial hypotheses
BRCA members w.r.t FANCD2
BRCA2 FANCD2
Table 5. 2nd order interaction ranking between FANCD2 VS RAD51 family members.
Table 5. 2nd order interaction ranking between FANCD2 VS RAD51 family members.
Ranking RAD51 members VS FANCD2
Ranking of RAD51 members w.r.t FANCD2
laplace linear rbf
RAD51 - FANCD2 885 1995 1383
RAD51AP1 - FANCD2 1734 644 1291
RAD51C - FANCD2 54 2399 2566
Table 6. 2nd order combinatorial hypotheses between FANCD2 and RAD51 family members.
Table 6. 2nd order combinatorial hypotheses between FANCD2 and RAD51 family members.
Unexplored combinatorial hypotheses
RAD51 members w.r.t FANCD2
RAD-51/51AP1 FANCD2
Table 7. 2nd order interaction ranking between FANCD2 VS ERCC family members.
Table 7. 2nd order interaction ranking between FANCD2 VS ERCC family members.
Ranking ERCC members VS FANCD2
Ranking of ERCC members w.r.t FANCD2
laplace linear rbf
ERCC8 - FANCD2 371 1951 997
ERCC6L - FANCD2 1209 520 1884
Table 8. 2nd order combinatorial hypotheses between FANCD2 and ERCC family members.
Table 8. 2nd order combinatorial hypotheses between FANCD2 and ERCC family members.
Unexplored combinatorial hypotheses
ERCC members w.r.t FANCD2
ERCC-8/6L FANCD2
Table 9. 2nd order interaction ranking between FANCD2 VS KIAA family members.
Table 9. 2nd order interaction ranking between FANCD2 VS KIAA family members.
Ranking KIAA members VS FANCD2
Ranking of KIAA members w.r.t FANCD2
laplace linear rbf
KIAA0586 - FANCD2 211 703 17
KIAA1524 - FANCD2 225 2578 481
KIAA1257 - FANCD2 749 1173 587
KIAA0020 - FANCD2 979 2291 1332
KIAA1324 - FANCD2 1466 413 1410
KIAA1731 - FANCD2 1549 1592 2223
KIAA1586 - FANCD2 1667 1233 277
KIAA0101 - FANCD2 2118 570 2103
KIAA1143 - FANCD2 2279 1094 2043
KIAA1244 - FANCD2 2341 777 2453
KIAA1430 - FANCD2 2468 1138 2075
Table 10. 2nd order combinatorial hypotheses between FANCD2 and KIAA family members.
Table 10. 2nd order combinatorial hypotheses between FANCD2 and KIAA family members.
Unexplored combinatorial hypotheses
KIAA members w.r.t FANCD2
KIAA-0586/1524/1257/0020/1324/1731/1586 FANCD2
Table 11. 2nd order interaction ranking between FANCD2 VS XRCC family members.
Table 11. 2nd order interaction ranking between FANCD2 VS XRCC family members.
Ranking XRCC members VS FANCD2
Ranking of XRCC members w.r.t FANCD2
laplace linear rbf
XRCC6BP1 - FANCD2 1720 1545 1200
XRCC2 - FANCD2 2002 111 1269
XRCC1 - FANCD2 2096 1096 2170
XRCC6 - FANCD2 2694 215 2539
Table 12. 2nd order combinatorial hypotheses between FANCD2 and XRCC family members.
Table 12. 2nd order combinatorial hypotheses between FANCD2 and XRCC family members.
Unexplored combinatorial hypotheses
XRCC members w.r.t FANCD2
XRCC-6BP1/2 FANCD2
Table 13. 2nd order interaction ranking between FANCD2 VS SMC family members.
Table 13. 2nd order interaction ranking between FANCD2 VS SMC family members.
Ranking SMC members VS FANCD2
Ranking of SMC members w.r.t FANCD2
laplace linear rbf
SMC1A - FANCD2 1156 88 1502
SMC4 - FANCD2 44 2042 83
SMC2 - FANCD2 229 2541 236
Table 14. 2nd order combinatorial hypotheses between FANCD2 and SMC family members.
Table 14. 2nd order combinatorial hypotheses between FANCD2 and SMC family members.
Unexplored combinatorial hypotheses
SMC members w.r.t FANCD2
SMC-1A/4/2 FANCD2
Table 15. 2nd order interaction ranking between FANCD2 VS WDR family members.
Table 15. 2nd order interaction ranking between FANCD2 VS WDR family members.
Ranking WDR members VS FANCD2
Ranking of WDR members w.r.t FANCD2
laplace linear rbf laplace linear rbf
WDR76 - FANCD2 34 2426 575 WDR62 - FANCD2 162 2485 765
WDR74 - FANCD2 344 501 615 WDR12 - FANCD2 403 1704 870
WDR77 - FANCD2 544 1480 402 WDR75 - FANCD2 563 805 1617
WDR36 - FANCD2 623 1641 1159 WDR43 - FANCD2 738 1775 1464
WDR91 - FANCD2 1069 1180 976 WDR35 - FANCD2 1162 1042 109
WDR92 - FANCD2 1228 2620 427 WDR18 - FANCD2 1234 924 2274
WDR3 - FANCD2 1562 344 1621 WDR89 - FANCD2 1662 1297 749
WDR41 - FANCD2 1709 2352 700 WDR70 - FANCD2 1825 1017 1849
WDR27 - FANCD2 1850 1609 602 WDR5 - FANCD2 2029 277 1561
WDR46 - FANCD2 2139 78 2500 WDR61 - FANCD2 2214 190 1741
WDR90 - FANCD2 2235 1462 785 WDR53 - FANCD2 2278 976 1627
Table 16. 2nd order combinatorial hypotheses between FANCD2 and WDR family members.
Table 16. 2nd order combinatorial hypotheses between FANCD2 and WDR family members.
Unexplored combinatorial hypotheses
WDR members w.r.t FANCD2
WDR-76/62/74/12/77/75/36/43 FANCD2
WDR-91/35/92/18/3/89/90 FANCD2
Table 17. 2nd order interaction ranking between FANCD2 VS UBE2 family members.
Table 17. 2nd order interaction ranking between FANCD2 VS UBE2 family members.
Ranking UBE2 members VS FANCD2
Ranking of UBE2 members w.r.t FANCD2
laplace linear rbf
UBE2G2 - FANCD2 137 1276 183
UBE2S - FANCD2 506 1347 635
UBE2T - FANCD2 689 266 1718
UBE2C - FANCD2 829 108 1505
Table 18. 2nd order combinatorial hypotheses between FANCD2 and UBE2 family members.
Table 18. 2nd order combinatorial hypotheses between FANCD2 and UBE2 family members.
Unexplored combinatorial hypotheses
UBE2 members w.r.t FANCD2
UBE2-G2/S/T/C FANCD2
Table 19. 2nd order interaction ranking between FANCD2 VS CDC family members.
Table 19. 2nd order interaction ranking between FANCD2 VS CDC family members.
Ranking CDC members VS FANCD2
Ranking of CDC members w.r.t FANCD2
laplace linear rbf laplace linear rbf
CDCA2 - FANCD2 133 2743 329 CDC25C - FANCD2 241 2677 76
CDC6 - FANCD2 386 1327 14 CDC25A - FANCD2 481 885 421
CDCA7L - FANCD2 818 1991 1111 CDCA8- FANCD2 909 1454 1220
CDCA4 - FANCD2 1206 1615 1651 CDCA5 - FANCD2 1224 2014 2491
CDC7 - FANCD2 1269 695 1147 CDCA7 - FANCD2 1696 862 1373
CDC20 - FANCD2 1950 1088 1552 CDC45 - FANCD2 2401 248 1988
CDC123 - FANCD2 2515 469 2429 CDCA3 - FANCD2 2626 664 2470
CDC23 - FANCD2 2671 206 1997
Table 20. 2nd order combinatorial hypotheses between FANCD2 and CDC family members.
Table 20. 2nd order combinatorial hypotheses between FANCD2 and CDC family members.
Unexplored combinatorial hypotheses
CDC members w.r.t FANCD2
CDC-A2/25C/6/25A/A7L/A8/7/A7 FANCD2
Table 21. 2nd order interaction ranking between FANCD2 VS IPO family members.
Table 21. 2nd order interaction ranking between FANCD2 VS IPO family members.
Ranking IPO members VS FANCD2
Ranking of IPO members w.r.t FANCD2
laplace linear rbf
IPO5 - FANCD2 418 1903 2055
IPO11 - FANCD2 1040 1863 40
IPO9 - FANCD2 2313 998 2085
Table 22. 2nd order combinatorial hypotheses between FANCD2 and IPO family members.
Table 22. 2nd order combinatorial hypotheses between FANCD2 and IPO family members.
Unexplored combinatorial hypotheses
IPO members w.r.t FANCD2
IPO-11 FANCD2
Table 23. 2nd order interaction ranking between FANCD2 VS ALDH family members.
Table 23. 2nd order interaction ranking between FANCD2 VS ALDH family members.
Ranking ALDH members VS FANCD2
Ranking of ALDH members w.r.t FANCD2
laplace linear rbf
ALDH3A1 - FANCD2 376 1971 543
ALDH5A1 - FANCD2 419 1502 1249
ALDH7A1 - FANCD2 581 1068 1352
ALDH1B1 - FANCD2 1846 262 1139
ALDH9A1 - FANCD2 2107 728 1157
ALDH3A2 - FANCD2 2563 357 2398
Table 24. 2nd order combinatorial hypotheses between FANCD2 and ALDH family members.
Table 24. 2nd order combinatorial hypotheses between FANCD2 and ALDH family members.
Unexplored combinatorial hypotheses
ALDH members w.r.t FANCD2
ALDH-3A1/5A1/7A1/1B1/9A1 FANCD2
Table 25. 2nd order interaction ranking between FANCD2 VS H2A family members.
Table 25. 2nd order interaction ranking between FANCD2 VS H2A family members.
Ranking H2A members VS FANCD2
Ranking of H2A members w.r.t FANCD2
laplace linear rbf
H2AFX (or H2AX) - FANCD2 593 324 2008
H2AFV - FANCD2 791 1329 1659
H2AFZ - FANCD2 1292 1921 634
Table 26. 2nd order combinatorial hypotheses between FANCD2 and H2A family members.
Table 26. 2nd order combinatorial hypotheses between FANCD2 and H2A family members.
Unexplored combinatorial hypotheses
H2A members w.r.t FANCD2
H2A-FX/FV/FZ FANCD2
Table 27. 2nd order interaction ranking between FANCD2 VS HSP family members.
Table 27. 2nd order interaction ranking between FANCD2 VS HSP family members.
Ranking HSP members VS FANCD2
Ranking of HSP members w.r.t FANCD2
laplace linear rbf laplace linear rbf
HSPE1 - FANCD2 336 1246 745 HSPD1 - FANCD2 385 388 617
HSPA4L - FANCD2 520 2211 2202 HSPB6 - FANCD2 1000 2421 520
HSPA9 - FANCD2 2078 370 1514 HSPA4 - FANCD2 2621 25 2650
Table 28. 2nd order combinatorial hypotheses between FANCD2 and HSP family members.
Table 28. 2nd order combinatorial hypotheses between FANCD2 and HSP family members.
Unexplored combinatorial hypotheses
HSP members w.r.t FANCD2
HSP-E1/D1/B6/A9 FANCD2
Table 29. 2nd order interaction ranking between FANCD2 VS CDK family members.
Table 29. 2nd order interaction ranking between FANCD2 VS CDK family members.
Ranking CDK members VS FANCD2
Ranking of CDK members w.r.t FANCD2
laplace linear rbf
CDK4 - FANCD2 918 1632 1890
CDK5RAP1 - FANCD2 1305 566 1196
CDK5RAP2 - FANCD2 2064 34 921
CDK6 - FANCD2 2463 337 1409
Table 30. 2nd order combinatorial hypotheses between FANCD2 and CDK family members.
Table 30. 2nd order combinatorial hypotheses between FANCD2 and CDK family members.
Unexplored combinatorial hypotheses
CDK members w.r.t FANCD2
CDK-6/5RAP1/5RAP2 FANCD2
Table 31. 2nd order interaction ranking between FANCD2 VS DNAH family members.
Table 31. 2nd order interaction ranking between FANCD2 VS DNAH family members.
Ranking DNAH members VS FANCD2
Ranking of DNAH members w.r.t FANCD2
laplace linear rbf
DNAH11 - FANCD2 762 1463 567
DNAH14 - FANCD2 1252 1703 229
Table 32. 2nd order combinatorial hypotheses between FANCD2 and DNAH family members.
Table 32. 2nd order combinatorial hypotheses between FANCD2 and DNAH family members.
Unexplored combinatorial hypotheses
DNAH members w.r.t FANCD2
DNAH-11/14 FANCD2
Table 33. 2nd order interaction ranking between FANCD2 VS FOX family members.
Table 33. 2nd order interaction ranking between FANCD2 VS FOX family members.
Ranking FOX members VS FANCD2
Ranking of FOX members w.r.t FANCD2
laplace linear rbf
FOXJ1 - FANCD2 830 2003 972
FOXD2-AS1 - FANCD2 1154 611 2023
FOXM1 - FANCD2 1868 44 1142
FOXA2 - FANCD2 2101 1184 2240
Table 34. 2nd order combinatorial hypotheses between FANCD2 and FOX family members.
Table 34. 2nd order combinatorial hypotheses between FANCD2 and FOX family members.
Unexplored combinatorial hypotheses
FOX members w.r.t FANCD2
FOX-J1/D2-AS1/M1 FANCD2
Table 35. 2nd order interaction ranking between FANCD2 VS RNF family members.
Table 35. 2nd order interaction ranking between FANCD2 VS RNF family members.
Ranking RNF members VS FANCD2
Ranking of RNF members w.r.t FANCD2
laplace linear rbf
RNF157-AS1 - FANCD2 399 533 1742
RNF166 - FANCD2 659 1764 526
RNF20 - FANCD2 1227 247 1331
RNF43 - FANCD2 1366 1571 2048
RNF26 - FANCD2 1476 873 1540
RNF144B - FANCD2 1504 1733 1095
RNF157 - FANCD2 1553 417 449
RNF220 - FANCD2 2716 14 2668
Table 36. 2nd order combinatorial hypotheses between FANCD2 and RNF family members.
Table 36. 2nd order combinatorial hypotheses between FANCD2 and RNF family members.
Unexplored combinatorial hypotheses
RNF members w.r.t FANCD2
RNF-157-AS1/166/20/26/144B/157 FANCD2
Table 37. 2nd order interaction ranking between FANCD2 VS E2F family members.
Table 37. 2nd order interaction ranking between FANCD2 VS E2F family members.
Ranking E2F members VS FANCD2
Ranking of E2F members w.r.t FANCD2
laplace linear rbf
E2F1 - FANCD2 200 1944 469
E2F2 - FANCD2 472 2345 140
E2F7 - FANCD2 482 2500 985
E2F8 - FANCD2 1873 192 582
E2F5 - FANCD2 2537 435 2079
Table 38. 2nd order combinatorial hypotheses between FANCD2 and E2F family members.
Table 38. 2nd order combinatorial hypotheses between FANCD2 and E2F family members.
Unexplored combinatorial hypotheses
E2F members w.r.t FANCD2
E2F-1/2/7/8 FANCD2
Table 39. 2nd order interaction ranking between FANCD2 VS SNHG family members.
Table 39. 2nd order interaction ranking between FANCD2 VS SNHG family members.
Ranking SNHG members VS FANCD2
Ranking of SNHG members w.r.t FANCD2
laplace linear rbf laplace linear rbf
SNHG3 - FANCD2 339 1259 1759 SNHG6 - FANCD2 551 1943 74
SNHG10 - FANCD2 866 1960 1442 SNHG5 - FANCD2 1140 1961 674
SNHG7 - FANCD2 1220 694 1862 SNHG17 - FANCD2 1524 454 1198
SNHG16 - FANCD2 1600 2275 882 SNHG15 - FANCD2 1669 1464 322
SNHG1 - FANCD2 1705 2006 1185 SNHG18 - FANCD2 2276 614 1734
SNHG8 - FANCD2 2407 1232 2160
Table 40. 2nd order combinatorial hypotheses between FANCD2 and SNHG family members.
Table 40. 2nd order combinatorial hypotheses between FANCD2 and SNHG family members.
Unexplored combinatorial hypotheses
SNHG members w.r.t FANCD2
SNHG-3/6/10/5/7/17/15 FANCD2
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